What about redox reactions with less powerful oxidants? Are all these reactions as favored as combustion?

Hardly so. Remember that in every redox reaction, an oxidizing and reducing agent react to form another oxidizing and reducing agent. Consider the following reaction:. This reaction can go either way and is reversible. The above form is written in the favored direction in anaerobic metabolism when both Pyr and NADH levels are high.

Although the ΔG 0 favors the oxidation of lactate, given the high concentration of Pyr and NADH, the reaction is driven in the opposite direction and proceeds as shown. The best enzymes to regulate are those that catalyze the first committed step in the reaction pathway.

These reactions often occur from key metabolic intermediates that are immediately before or proximal to branches in reaction pathways.

In reality, metabolic regulation is more complex and is distributed to many steps in a reaction pathway in ways that might not be evident without details mathematical analyses. We will discuss that in the next sections on metabolic control analysis.

Fundamentals of Biochemistry Vol. II - Bioenergetics and Metabolism. jpg" ]. Search site Search Search. Go back to previous article. Sign in. II - Bioenergetics and Metabolism Principles of Metabolic Regulation Changing the activity of a pre-existing enzyme The quickest way to modulate the activity of an enzyme is to alter the activity of an enzyme that already exists in the cell.

The list below, illustrated in the following figure, gives common ways to regulate enzyme activity Substrate availability : Substrates reactants bind to enzymes with a characteristic affinity characterized by a dissociation constant and a kinetic parameter called Km units of molarity.

If the actual concentration of a substrate in a cell is much less than the Km, the activity of the enzyme is very low. If the substrate concentration is much greater than Km, the enzyme's active site is saturated with substrate and the enzyme is maximally active.

Product inhibition : A product of an enzyme-catalyzed reaction often resembles a starting reactant, so it should be clear that the product should also bind to the activity site, albeit probably with lower affinity. Under conditions in which the product of a reaction is present in high concentration, it would be energetically advantageous to the cell if no more product was synthesized.

Product inhibition is hence commonly observed. Likewise, it is energetically advantageous to a cell if the end product of an entire pathway could likewise bind to the initial enzyme in the pathways and inhibit it, allowing the whole pathway to be inhibited. This type of feedback inhibition is commonly observed.

Molecules that bind to sites on target enzymes other than the active site allosteric sites can regulate the activity of the target enzyme. These molecules can be structurally dissimilar to those that bind at the active site. They do so by conformational changes which can either activate or inhibit the target enzyme's activity.

pH and enzyme conformation : Changes in pH that can accompany metabolic processes such as respiration aerobic glycolysis for example can alter the conformation of an enzyme and hence enzyme activity.

The initial changes are covalent change in the protonation state of the protein which can lead to an alteration in the delicate balance of forces that affect protein structure. pH and active site protonation state : Changes in pH can affect the protonation state of key amino acid side chains in the active site of proteins without affecting the local or global conformation of the protein.

Catalysis may be affected if the mechanism of catalysis involves an active site nucleophile for example , that must be deprotonated for activity. Covalent modification : Many if not most proteins are subjected to post-translational modifications which can affect enzyme activity through local or global shape changes, by promoting or inhibiting binding interaction of substrates and allosteric regulators, and even by changing the location of the protein within the cell.

Proteins may be phosphorylated, acetylated, methylated, sulfated, glycosylated, amidated, hydroxylated, prenylated, or myristoylated, often in a reversible fashion. Some of these modifications are reversible. Regulation by phosphorylation through the action of kinases, and dephosphorylations by phosphates are extremely common.

Control of the phosphorylation state is mediated through signal transduction processes starting at the cell membrane, leading to the activation or inhibition of protein kinases and phosphatases within the cell. Copyright; author via source.

Regulation of single enzymes or entire pathways: Enzyme condensates Single enzymes or all the enzymes of a given pathway can be coordinately regulated to maximize end-product output by organizing the enzymes in one large complex built from soluble enzymes that produce a "condensate" through a process similar to phase separation.

The figure shows metabolism-related enzymes that form polymers in various organisms. Changing the amount of an enzyme Another longer-duration method to modulate the activity of an enzyme is to alter the activity of an enzyme that already exists in the cell.

These changes result from the recruitment of transcription factors proteins to DNA sequences that regulate the transcription of the enzyme gene. Degradation of messenger RNA for the enzyme: The levels of messenger RNA for a protein will directly determine the amount of that protein synthesized.

Small inhibitor RNAs, derived from microRNA molecules transcribed from cellular DNA, can bind to specific sequences in the mRNA of a target enzyme. The resulting double-stranded RNA complex recruits an enzyme Dicer that cleaves the complex with the effect of decreasing the translation of the protein enzyme from its mRNA.

Some proteins are synthesized in a "pre" form which must be cleaved in a targeted and limited fashion by proteases to activate the protein enzyme. Some proteins are not fully folded and must bind to other factors in the cell to adopt a catalytically active form.

The presence of the negatively-charged phosphate in the molecule also prevents the sugar from leaving the cell. When hexokinase is inhibited, glucose diffuses out of the cell and does not become a substrate for the respiration pathways in that tissue. The product of the hexokinase reaction is glucosephosphate, which accumulates when a later enzyme, phosphofructokinase , is inhibited.

Phosphofructokinase is the main enzyme controlled in glycolysis. Specifically, ATP binds an allosteric site on the enzyme to inhibit its activity.

An increase in citrate concentration can occur because of a blockage in the citric acid cycle. Fermentation, with its production of organic acids like lactic acid, frequently accounts for the increased acidity in a cell; however, the products of fermentation do not typically accumulate in cells.

The last step in glycolysis is catalyzed by pyruvate kinase. The pyruvate produced can proceed to be catabolized or converted into the amino acid alanine. If no more energy is needed and alanine is in adequate supply, the enzyme is inhibited. Recall that fructose-1,6-bisphosphate is an intermediate in the first half of glycolysis.

The regulation of pyruvate kinase involves phosphorylation, resulting in a less-active enzyme. Dephosphorylation by a phosphatase reactivates it. Pyruvate kinase is also regulated by ATP a negative allosteric effect.

If more energy is needed, more pyruvate will be converted into acetyl CoA through the action of pyruvate dehydrogenase. If either acetyl groups or NADH accumulates, there is less need for the reaction and the rate decreases.

Pyruvate dehydrogenase is also regulated by phosphorylation: a kinase phosphorylates it to form an inactive enzyme, and a phosphatase reactivates it. The kinase and the phosphatase are also regulated. The gluconeogenesis involves the enzyme fructose 1,6-bisphosphatase that is regulated by the molecule citrate an intermediate in the citric acid cycle.

Increased citrate will increase the activity of this enzyme. Gluconeogenesis needs ATP, so reduced ATP or increased AMP inhibits the enzyme and thus gluconeogenesis. Type 2 diabetes mellitus.

Diabetes and hyperglycemia. Fat metabolism deficiencies. Phosphofructokinase : any of a group of kinase enzymes that convert fructose phosphates to biphosphate.

Glycolysis : the cellular metabolic pathway of the simple sugar glucose to yield pyruvic acid and ATP as an energy source. Kinase : any of a group of enzymes that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific target molecules substrates ; the process is termed phosphorylation.

Glucose : a simple monosaccharide sugar with a molecular formula of C 6 H 12 O 6 ; it is a principal source of energy for cellular metabolism.

Hexokinase: an enzyme that phosphorylates hexoses six-carbon sugars , forming hexose phosphate. Pyruvate: a biological molecule that consists of three carbon atoms and two functional groups — a carboxylate and a ketone group.

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Each DNA binding domain includes the core peptide motif Pro-Arg-Gly-Arg-Pro P-R-G-R-P Figure 1 , through which HMGA1 preferentially interacts with the minor groove of AT-rich DNA sequences 34 , Although all three AT-hook motifs synergize during target recognition, the first two AT-hooks contribute to the majority of HMGA1 affinity for DNA The two different HMGA1 isoforms may have different biological functions, as indicated by studies in MCF-7 breast epithelial cells, where HMGA1b forced expression confers a more aggressive neoplastic phenotype than HMGA1a However, in the context of other cell lines or of other biological processes, including metabolism, more investigations are needed to deepen this issue.

Being among the most abundant non-histone, chromatin-associated protein, HMGA1 has been shown to cooperate with other nuclear proteins, including the chaperone nucleophosmin 38 , and to play a role in the chromatin organization by an interplay with histones 39 , The functional activity of HMGA1 relies on a complex and fine regulation of its own expression.

Down-regulation of some of these microRNAs—miR15, miR, miR26, miRa-2, and let-7—have been described to cause increased levels of HMGA1 in pituitary adenomas Interestingly, some of the same miRNAs involved in tumorigenesis also play a role in metabolism. For example, miRa has been shown to target key regulators of insulin signaling and glucose metabolism in the liver, while its impairment is associated with hepatic oncogenesis and metabolic disorders Processed pseudogenes are non-functional copies of normal genes generated by a process of mRNA retrotransposition.

Compared with homologous normal genes, they lack introns and contain single nucleotide substitutions, deletions, insertions, and residues of poly A tails 45 , Human genome includes thousands of pseudogenes, accumulated during evolution 45 , However, although our actual knowledge about the real biological role of pseudogenes is still limited, increasing evidences exist, supporting a functional significance for these macromolecules So far, eight HMGA1 pseudogenes have been described Some of them act on the stability of HMGA1 mRNA or prevent miRNAs from targeting HMGA1 mRNA, thereby behaving as competing endogenous RNAs ceRNAs.

The RNA encoded by one of them, the HMGA1-p pseudogene, by effectively competing for the trans-acting cytoplasmic protein αCP1, accelerates the degradation of mRNA from the homolog normal gene, thereby reducing the longevity of HMGA1 mRNA transcript Some pseudogenes display aminoacid sobstitutions at the level of specific aminoacid residues that in the native HMGA1 are subjected to post-translational modifications involved in the modulation of HMGA1's activities.

An intriguing possibility is that, if expressed, these proteins could compete with the native HMGA1, escaping the modulatory effects of these post-translational modifications that strongly impact on HMGA1 ability for chromatin remodeling and protein-protein interactions A variety of extracellular and intracellular signals can induce different PTMs on HMGA1 protein, which influence its ability to interact with either DNA or proteins, thereby affecting HMGA1 nuclear function 8 , PTMs include phosphorylation, methylation, and acetylation 8 , 12 , 49 , Generally, increased level of HMGA1 phosphorylation reduces DNA-binding affinity and transcriptional activation, and this status correlates with an elevated residence time of the HMGA1a isoform in the repressed inactive heterochromatin, rather than in the active euchromatin In detail, phosphorylation can affect different serine Ser and threonine Thr residues.

The phosphorylation at Thr and Thr by the cell-cycle dependent kinase cdc2 results in decreased binding of HMGA1a to DNA 51 , The same effect is produced following the phosphorylation of HMGA1a at Ser and Ser by the protein kinase C PKC pathway The acidic C-terminal tail of HMGA1 is constitutively phosphorylated.

At this level, the protein kinase CK2 catalyzes the phosphorylation of Ser, Ser, and Ser of HMGA1a 54 , while it has been demonstrated that phosphorylation of the C-terminal tail has structural consequences on HMGA1 compactness HMGA1 is also susceptible to acetylation on several lysine residues Acetylation at Lys, by CBP, destabilizes the enhanceosome formation on the human interferon beta IFN-beta gene, leading to transcriptional inhibition of this gene; on the contrary, PCAF-induced acetylation at Lys increased the transcription of the IFN-beta gene through enhanceosome stabilization HMGA1 is also methylated at several residues located exclusively within the AT-hook motifs.

Although the significance of this type of PTM is still largely unknown, methylation at the AT-hook motifs indicate a potential role for methylation in regulating HMGA1-DNA binding activity 12 , 49 , 57 — HMGA1 is highly expressed during embryogenesis, suggesting its critical role during the embryonic development It is also highly expressed in adult stem cells, including intestinal and hematopoietic stem cells The important role of HMGA1 at these levels is supported by phenotypic studies in Hmga1- knockout mice, indicating that mice lacking HMGA1 develop cardiomyopathy, aberrant hematopoiesis, and defective pancreatic beta cell development 19 , Also, HMGA1 plays a role in adipogenesis, and myogenesis, although its levels decrease before terminal cell differentiation 63 , Vice versa, overexpression of HMGA1 is found in a wide range of human cancers, including prostate, thyroid, colon, breast, lung, bladder, pancreas, stomach, kidney, uterus, and hepatocellular carcinomas, as well as non-melanoma skin cancers, and hematopoietic malignancies 10 , 14 , 65 , In some of these cancers, HMGA1 expression strongly correlates with an advanced stage, the metastatic potential and reduced survival.

Poorer prognosis is due to the fact that HMGA1 promotes the transcription of many genes involved in tumor growth, invasion, migration, neoangiogenesis, epithelial-mesenchymal transition and cancer metastasis 8 , 10 , 67 — Nevertheless, it has been also reported that HMGA1 can have anti-oncogenic effects, depending on the cellular context This bivalent function proves the relevance of HMGA1 in both physiological and pathological conditions and explains the reason why HMGA1 requires a fine-tuned spatio-temporal expression and activity modulation.

HMGA1 regulates cell cycle-related chromosomal changes, DNA replication and repair, and molecular chaperoning 11 , 38 , Also, by inducing a more open chromatin state, HMGA1 assists gene transcription 8 , HMGA1 performs this task by interacting with a large variety of activating or inhibiting transcription factors and orchestrating their assembly on promoter regions.

The enhanceosome model provides one of the best-understood examples of how HMGA1 can interact with other transcription factors, leading to a highly specific activation of gene transcription in higher eukaryotes 76 , In this sense, enhanceosome formation over the IFN-beta promoter 75 , 77 or the INSR promoter 15 is of paradigmatic importance.

In relation to protein-protein interactions, the HMGA1 network has been reported to be very wide 78 , 79 , as HMGA1 has been shown to physically and functionally interact with many ubiquitous and tissue-specific transcription factors. The potential interplay of HMGA1 with other nuclear metabolic sensors, such as ChREBP, SREBP1-c, FoxO family members, and PGC-1, instead, has not yet been investigated.

Figure 2. HMGA1 as facilitator of enhanceosome formation. HMGA1 binds to the enhancer region through its DNA-binding domain, while interacting with other transcription factors in the promoter, forming a multiprotein-DNA complex that enhances gene transcription.

The scheme refers to activation of the INSR gene. Emerging lines of evidence indicate that HMGA1 interacts also with different RNAs.

The first evidence supporting a specific RNA affinity of HMGA1 has been reported in studies pointing to a role of HMGA1 during the exon skipping of presenilin-2 pre-mRNA, which resulted in the production of a deleterious protein isoform causing sporadic Alzheimer's disease More recently, a new interaction has been reported between HMGA1 and the nuclear non-coding 7SK RNA 83 , a factor which negatively affects Polymerase II transcription elongation and influences HMGA1 biological functions by competing for the first AT-hook binding with DNA Also, through the first AT-hook, HMGA1 has been shown to interact with the origin recognition complex, thus playing a key role in DNA replication The peptide hormone insulin exerts its biological effects by binding to the INSR, a specific tyrosine kinase receptor glycoprotein located in the plasma membrane of insulin target cells.

As a key regulator of insulin action, many studies have explored the INSR gene 86 , Nuclear binding proteins that recognized the INSR promoter were initially identified during muscle and adipose cell differentiation in the context of two AT-rich sequences of the regulatory region of the INSR gene Using conventional chromatographic purification methods, combined with electrophoretic mobility shift assays and immunoblots, these proteins were identified as HMGA1, while reporter gene analysis findings showed that HMGA1 is required for proper transcription of the INSR gene In support of the role of HMGA1 in INSR gene transcription, in vitro investigations in beta-pancreatic cells demonstrated that sustained hyperglycemia impaired HMGA1 expression, a condition affecting INSR content in beta cells and, thus, insulin secretion These observations, which were based mainly on in vitro analyses, were substantiated by studies in vivo , in Hmga1- knockout mice, in which a marked decrease in INSR gene and protein expression was observed in the major targets of insulin action, contributing to a phenotype characteristic of human type 2 diabetes Subsequent investigations revealed that other transcription factors, such as the activating protein 2 AP2 and PPARgamma, can influence INSR gene transcription in a variety of cell types 81 , 91 , while studies in cultured myocytes aimed at deciphering the mechanisms by which free fatty acid FFA contribute to the development of insulin resistance and type 2 diabetes, showed that FFA can impair INSR expression and insulin signaling and sensitivity by affecting HMGA1 92 — In particular, FFA induce phosphorylation and nuclear translocation of the protein kinase C epsilon type PKCepsilon.

In the nucleus, PKCepsilon phosphorylates HMGA1 and downregulates its expression by deactivating the transcription factor Sp1, thereby attenuating INSR gene expression by direct and indirect mechanisms, which in turn compromise insulin action and sensitivity 92 — Altogether, these findings clearly indicate that HMGA1 is a crucial component of the insulin signaling pathway, and plays an important role in INSR gene expression in insulin target tissues.

A direct role of HMGA1 in insulin production and pancreatic islet development and beta cell function has been postulated starting from the observation that, compared to wild-type littermates, Hmga1- knockout mice showed decreased insulin secretion and reduced beta cell mass On the other hand, a functional interplay between HMGA1 and the homeodomain transcription factor PDX-1 a key regulator of pancreatic islet development and beta cell function has been shown previously in the context of the INS gene and other pancreatic islet-specific genes The possibility for HMGA1 to play a role also in this context, was substantiated by the fact that binding of PDX-1 to the INS gene promoter was reduced in Hmga1- knockout mice Subsequent studies added more details in our understanding of the INS gene regulation.

In the insulin-secreting beta-cell line INS-1, as demonstrated by chromatin immunoprecipitation experiments, glucose stimulated binding of HMGA1 to the INS promoter, resulting in a significant increase in insulin production and secretion Coherently, when INS-1 cells were treated with HMGA1 siRNA, a significant reduction in glucose-induced insulin secretion was observed, thereby confirming the importance of HMGA1 in this scenario Even in the absence of HMGA1-DNA binding sites on the INS gene promoter, the assembly of a transcriptionally active multiprotein-DNA complex involving HMGA1, PDX-1 and the transcription factor MafA, was required for proper transcription of both human and mouse INS genes In line with this observation, the deficit in HMGA1 compromised binding of PDX-1 and MafA to the INS promoter, thereby imparing INS gene transcription and glucose-induced insulin secretion However, given that substantial interspecies differences exist in pancreatic islet development and function 19 , 97 , 98 , any parallelism between human and mouse at this level must be considered carefully and further details on this should be provided.

For example, based on our recent observations highlighting a novel relationship between HMGA1 and FoxO1 99 , further investigation in this field could deliver deeper information on the possibility that an interplay among HMGA1 and FoxO1 can be a component of this regulation, as an overarching role of FoxO1 in pancreatic beta cell function has been already outlined 6 , — Besides being required for both insulin and INSR gene transcription, HMGA1 plays an important role in the regulation of the insulin signaling cascade The gluconeogenic genes phosphoenolpyruvate carboxykinase PEPCK and glucosephosphatase G6Pase , as well as the IGFBP1 gene which plays a glucose counterregulatory role by preventing the potential hypoglycemic effects of IGF1 are known to be inhibited by insulin for example, after a meal.

In fact, by triggering the phosphorylation of HMGA1 at the level of the three serine residues, Ser, Ser, and Ser, insulin promotes the detachment of HMGA1 from promoter target genes and its corresponding nuclear localization in the inactive heterochromatin.

Thus, HMGA1 acts as a downstream modulator of insulin action, and is an important key player in insulin and nutritionally-regulated transcription of genes involved in glucose metabolism and homeostasis.

Given that the role of the transcription factor FoxO1 in the control of gluconeogenesis is well established 6 , , as for the regulation of pancreatic beta cell function, a cross-talk between HMGA1 and FoxO1 can be hypothesized also in this case and investigated in future studies.

Data from the Hmga1 -knockout mouse model evidenced a complex metabolic phenotype, in which peripheral insulin hypersensitivity paradoxically coexisted with a condition of impaired glucose tolerance and overt diabetes 19 , thus supporting the existence of alternative insulin signaling pathways ensuring peripheral glucose utilization and disposal by insulin-independent mechanisms.

Further studies in vitro confirmed that HMGA1 has a role in the activation of both IGFBP1 and IGFBP3 gene transcription 16 , Therefore, it is plausible that under physiological circumstances e. The counter-regulatory hormone glucagon, which acts in opposition to insulin, binds its cognate G-protein coupled receptor on liver cell membrane and stimulates the transmembrane adenylyl cyclase to produce cyclic AMP cAMP as second messenger.

This, in turn, leads to the activation of protein kinase A PKA , which, among many other proteins, phosphorylates the Cyclic AMP Responsive Elements Binding Protein CREB transcription factor , The final event is the assembly of a functional transcriptional machinery on the promoter regions of gluconeogenic genes Some observations in cultured hepatic cells indicate that cAMP also increases HMGA1 protein expression 17 , Consistently, Hmga1 RNA levels were significantly increased in liver of mice following systemic administration of glucagon.

In agreement with the observations mentioned above, upregulation of FoxO1 expression via the glucagon-cAMP-PKA signaling has been reported in liver of fasting mice to maintain fasting euglycemia Thus, upregulation of HMGA1 during fasting when glucagon peaks may contribute to the mechanisms necessary to prevent hypoglycemia, through activation of FoxO1 99 and gluconeogenic gene expression.

The opposite occurs after a meal, when insulin peaks, and glucagon declines Figure 3. In this metabolic scenario, inactivation of HMGA1 by insulin-induced HMGA1 phosphorylation, by causing the detachment of FoxO1 from DNA and its nuclear exclusion, inhibits gluconeogenesis and contributes to restoration of postprandial euglycemia Figure 3.

Figure 3. The increase of glucagon during fasting Left turns on the cAMP-PKA-CREB pathway, allowing HMGA1 gene activation and protein expression. In turn, HMGA1 activates the FoxO1 gene and promotes transactivation of G6Pase and IGFBP1 promoters by FoxO1, thereby maintaining fasting euglycemia through elevation of hepatic gluconeogenesis and attenuation of IGF1 bioactivity.

Under feeding conditions Right , binding of insulin to its receptor initiates a series of events culminating in the sequential phosphorylation p of HMGA1 and FoxO1, which reduces FoxO1 gene expression, promotes the detachment of FoxO1 from G6Pase and IGFBP1 gene promoters, and leads to FoxO1 nuclear exclusion, thereby ensuring postprandial euglycemia through inhibition of hepatic gluconeogenesis and augmentation of IGF1 bioactivity.

In a recent paper, after 3-day fasting or restriction diet in mice, renal gene expression, assayed by microarray, demonstrated, among other transcription factors, an increment in HMGA1 expression These findings are coherent with previous findings in the liver, in which an effect of HMGA1 on gluconeogenic genes has been described Another glucose metabolism-related gene, which has been shown to be regulated by HMGA1, is the one encoding for the retinol binding protein 4 RBP RBP-4 is mostly produced by the liver, although adipose tissue also contributes, and plays a role in systemic insulin resistance.

RBP-4 expression in fat and its levels in blood inversely correlated with the adipose-specific glucose transporter GLUT-4 in obesity and type 2 diabetes In vitro studies with human HepG2 and murine Hepa 1 hepatoma cells have demonstrated that HMGA1 binds to and increases transcription of the RBP-4 gene promoter both in basal and in cAMP-induced conditions 17 , , while in vivo , in whole mice, injection of glucagon, by inducing increased intracellular cAMP, activates both HMGA1 and RBP-4 expression in liver and fat.

Consequently, under physiological circumstances, this loop has an important relapse in conditions of low glucose availability, in which intracellular cAMP increases. Interestingly, the brain-type GLUT-3 facilitative glucose transporter has also been shown to be transcriptionally regulated by HMGA1 , thereby supporting further the relevance of this factor in multiple settings of energy demand.

Both muscle and fat play relevant roles in maintaining euglycemia. In this regard, previous studies from our group demonstrated that INSR expression is reduced in muscle and adipose tissues from both Hmga1 -knockout mice and in individuals with reduced levels of HMGA1 19 , The physiological role of HMGA1 in adipogenesis has been investigated in vitro and in vivo 63 , , and a critical role of HMGA1 in adipocytic cell growth and differentiation has been demonstrated in murine 3T3-L1 adipocytes Also, HMGA1 may exert a negative role in adipose cell growth by balancing the effects of the cognate HMGA2 protein, another member of the HMGA family Indeed, transgenic mice, overexpressing HMGA1 in both white and brown adipose tissues, showed reduced fat mass and impaired adipogenesis with respect to wild-type mice 63 , and were protected against high-fat diet induced obesity and systemic insulin resistance, thus supporting the role of HMGA1 in the maintenance of glucose homeostasis.

In addition to RBP-4, whose regulation has been discussed, other adipokines have been demonstrated to be under the control of HMGA1. Several reports have also indicated that HMGA1 plays a role in muscle tissue, and HMGA1 is present in mouse C2C12 cultured muscle cells, in which HMGA1 overexpression increases cell proliferation and prevents myotube formation Downregulation of HMGA1 is an early and necessary step for the progression of the myogenic program.

In fact, mice overexpressing Lin28a and Lin28b show an insulin-sensitized state, with protection against high-fat diet induced diabetes In contrast, muscle-specific loss of Lin28a and overexpression of let-7 resulted in insulin resistance and impaired glucose tolerance As Lin28a directly promotes HMGA1 translation , it has been postulated that in muscle-specific Lin28a knockout mice, insulin resistance is, at least in part, due to reduced HMGA1 levels and consequently impaired INSR expression Insulin resistance, defined as a subnormal biological response to the glucose-lowering effect of insulin, is a characteristic of many common disorders, including type 2 diabetes, the metabolic syndrome, fatty liver disease, and obesity — However, severe forms of insulin resistance may occur as uncommon syndromes, either congenital or acquired, in patients with impaired INSR signaling or lipodistrophy , Congenital disorders include the Type A syndrome of insulin resistance, the Rabson-Mendenhall syndrome, leprechaunism, and some syndromes of generalized or partial lipodystrophy.

Type A syndrome is an autosomal dominant disorder characterized by the triad of hyperinsulinemia, acanthosis nigricans, and ovarian hyperandrogenism — Hyperglycemia is not always present at diagnosis.

Female patients appear lean and without lipodystrophy, even if a variant of this syndrome has been reported in obese women , Male patients may initially exhibit acanthosis nigricans and hypoglycemia, while overt diabetes may not occur until the fourth decade or later As a step toward understanding the molecular basis of regulation of the INSR gene, a nuclear binding protein that specifically interacted with, and activated the INSR gene promoter, was identified previously, during muscle and adipose cell differentiation Later, this DNA binding protein was identified as HMGA1, and its expression was markedly reduced in two unrelated patients with either the Type A syndrome or the common form of type 2 diabetes, in whom cell surface INSRs were decreased and INSR gene transcription was impaired despite the fact that the INSR genes were normal, thus indicating defects in INSR gene regulation 15 , 89 , Subsequent investigations in both these patients allowed the identification of a novel genetic variant, c.

In other two patients mother and daughter with the type A syndrome of insulin resistance, a hemizygous deletion of the HMGA1 gene was also identified Restoration of HMGA1 protein expression in these subjects' cells enhanced INSR gene transcription and restored cell-surface INSR protein expression, thus confirming that defects in HMGA1, by decreasing INSR protein production may indeed induce severe insulin resistance The mechanistic linkage between HMGA1, insulin resistance and certain less common forms of type 2 diabetes has been further supported by a study in two diabetic patients, in whom aberrant expression of a pseudogene for HMGA1, HMGA1-p , caused destabilization of HMGA1 mRNA with consequent loss of INSR and generation of insulin resistance These findings demonstrate, therefore, that HMGAl is necessary for proper expression of the INSR.

In its common form, type 2 diabetes is a heterogeneous complex disease in which concomitant insulin resistance and beta-cell dysfunction lead to hyperglycemia , From a pathogenetic point of view, both predisposing genetic factors and precipitating environmental factors contribute importantly to the development of the disease , So far, about gene variants have been associated with an increased risk for type 2 diabetes Most of these variants are presumed to negatively affect pancreatic beta-cell function and insulin secretion, while some of them appear to impact peripheral insulin sensitivity, thereby impairing tissue glucose uptake As it concerns HMGA1, on the basis of its involvement in insulin resistance, a role for this nuclear factor in type 2 diabetes has also been postulated and studies in this direction have been performed by us and others 20 , — In circulating monocytes and cultured lymphoblasts from diabetic patients carrying these variants, HMGA1 and INSR expressions were markedly decreased and these defects were corrected by transfecting HMGA1 cDNA The most frequent HMGA1 rs variant previously named rs , was significantly higher in type 2 diabetic patients from three populations of white European ancestry: Italian, American and French populations Although not replicated in a heterogeneous French population , the rs variant was later associated with type 2 diabetes among Chinese and Americans of Hispanic ancestry , thus providing evidence for the implication of the HMGA1 gene locus as one conferring a cross-race risk for the development of type 2 diabetes.

More recently, the credibility of an association between the HMGA1 rs variant and type 2 diabetes was confirmed also in a transethnic meta-analysis that included all available published articles examining this association in different populations The metabolic syndrome is a common multicomponent disorder, which is associated with increased risk for type 2 diabetes, cardiovascular disease CVD , and nonalcoholic fatty liver disease , As insulin resistance plays a pivotal role in the pathophysiology of metabolic syndrome , , the impact of HMGA1 has been investigated in two large Italian and Turkish populations, both affected by metabolic syndrome Findings indicated that the HMGA1 rs variant was significantly associated with metabolic syndrome in both populations, in which this association occurred independently of type 2 diabetes, thus lending credence to the hypothesis that this variant may independently associate with other insulin resistance-related traits.

Consistent with this assumption, a strong association of the rs variant with certain metabolic syndrome-related traits i. Interestingly, as CVD is a major risk for both type 2 diabetes and the metabolic syndrome, the association of HMGA1 rs variant with acute myocardial infarction, independently from diabetes and other cardiovascular risk factors, has been reported previously , , suggesting that HMGA1 may also represent a novel genetic marker of cardiovascular risk.

An important issue that deserves to be discussed is to which extent Hmga1 -knockout mice reflect findings in humans. Although in the broader context of glucose metabolism similarities between the two species are well known i.

At a molecular level, previous known beta cell species-specificities in ion channel components and membrane transporters, as well as in insulin secretion, have been recently further enriched by data from transcriptome profiles in single human and murine beta cells , , while evidence of heterogeneity of pancreatic beta cells has been proved to occur in both humans and mice However, interspecies differences do not exclude that in some instances, like in the case of lack of the KCNJ11 gene, the mouse phenotype well recapitulates human neonatal diabetes Focusing on HMGA1 loss-of-function, three biochemical and metabolic conditions are common to humans and mice: reduced insulin receptor expression, impaired insulin signaling, and insulin resistant diabetes.

Instead, insulin levels in humans hyperinsulinemic and mice hypoinsulinemic are clearly discrepant In fact, in Hmga1 -knockout mice, both beta cell mass and insulin secretion are impaired.

Differences in pancreatic islet ontogenesis and differentiation, as well as differences in nongenetic environmental elements and susceptibility to genetic modifiers, have been postulated to explain these dissimilarities On the other hand, Hmga1 -knockout mice have proved to be insulin hypersensitive, despite the deficit in INSRs.

Although the latter has proved to be more effective to reduce glycemia in mice than in humans , the importance of these systems in both species still deserves further investigations. As an example, recent findings obtained in genetically engineered mice with a specific deletion of the RBP4 gene in the liver, indicating that circulating RBP4 derives mainly from hepatocytes , need to be confirmed in humans.

At present, HMGA1 is known to be involved in multiple biological processes. Based on the above-mentioned findings, among the many tasks that HMGA1 can perform, there is its role in the transcriptional regulation of gene and gene networks involved in INSR signaling and glucose metabolism.

In this review, we provided an overview of the major contributions that have been made in this area over the last years. Overall, the data obtained so far well support the role of HMGA1 in the regulation of genes implicated in the maintenance of glucose homeostasis and metabolic control, providing new insight into the regulation of glucose metabolism and disposal.

Clinically, the importance of HMGA1 gene variability in glucose metabolism is emphasized in a wide range of clinical conditions ranging from rare insulin resistance syndromes to type 2 diabetes and the metabolic syndrome.

Besides, being a multifunctional protein, HMGA1 may constitute a molecular link between metabolism and other distinct biological processes, including cell proliferation, and differentiation, viability, autophagy, cell cycle, apoptosis, that need to be sustained by cell energy.

New insights may come from epigenetic studies, including miRNAs, whose common role in both malignancy and metabolism is recently emerging. On the other hand, disentangling the pleiotropic nature of HMGA1 by the identification of distinct molecular partners and networks uniquely implicated in metabolism, still represents a big challenge.

A contribution could come from studies on the relationship between HMGA1 and the yet unexplored nuclear metabolic sensors.

Apart from the intrinsic biological and clinical interest of these findings, a deeper understanding of the mechanisms that regulate glucose metabolism in health and disease is of importance for the development of more effective therapies.

To fill the gap of our knowledge in this regard, future directions based on the omics-related technologies, combined with bioinformatic tools, can help identify novel proteins and their networks, as well as genes and gene products regulated by, or interacting with HMGA1.

To the best of our knowledge, this is the first review article exclusively dedicated to the role of HMGA1 in this context, and we hope that it will serve as a quickly accessible reference in this important clinical field.

EC and DF prepared the first draft of the manuscript. RS, SP, MG, and GM contributed to critical revision of the manuscript. BA and FB were involved in the literature search.

AB critically revised and edited the final version of the manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor is currently co-organizing a Research Topic with one of the authors AB, and confirms the absence of any other collaboration.

Gerich JE. Physiology of glucose homeostasis. Diabetes Obes Metab. doi: PubMed Abstract CrossRef Full Text Google Scholar. Dashty M.

A quick look at biochemistry: carbohydrate metabolism. Clin Biochem. Desvergne B, Michalik L, Wahli W. Transcriptional regulation of metabolism. Physiol Rev. Kitamura T.

The role of FOXO1 in beta-cell failure and type 2 diabetes mellitus. Nature Rev Endocrinol. CrossRef Full Text Google Scholar. Nakae J, Park B-C, Accili D. Insulin stimulates phosphorylation of the forkhead transcription factor FKHR on serine through a Wortmannin-sensitive pathway. J Biol Chem. Accili D, Arden KC.

FoxOs at the crossroads of cellular metabolism, differentiation, and transformation. Cell —6. Cleynen I, Van and de Ven WJ. The HMGA proteins: a myriad of functions Review. Int J Oncol. Reeves R, Beckerbauer L. Biochim Biophys Acta — Wisniewski JR, Schwanbeck.

Int J Mol Med. Sumter TF, Xian Huso T, Koo M, Chang YT, Almasri TN, et al. The high mobility group A1 HMGA1 transcriptome in cancer and development. Curr Mol Med. Sgarra R, Zammitti S, Lo Sardo A, Maurizio E, Arnoldo L, Pegoraro S, et al.

HMGA molecular network: from transcriptional regulation to chromatin remodeling. Sgarra R, Diana F, Rustighi A, Manfioletti G, Giancotti V. Increase of HMGA1a protein methylation is a distinctive characteristic of leukaemic cells induced to undergo apoptosis.

Cell Death Differ. Diana F, Sgarra R, Manfioletti G, Rustighi A, Poletto D, Sciortino MT, et al. A link between apoptosis and degree of phosphorylation of high mobility group A1a protein in leukemic cells. Resar LM. The high mobility group A1 gene: transforming inflammatory signals into cancer?

Cancer Res. Foti D, Iuliano R, Chiefari E, Brunetti A. Mol Cell Biol. Iiritano S, Chiefari E, Ventura V, Arcidiacono B, Possidente K, Nocera A, et al.

Mol Endocrinol. Bianconcini A, Lupo A, Capone S, Quadro L, Monti M, Zurlo D, et al. Int J Biochem Cell Biol. Arcidiacono B, Iiritano S, Chiefari E, Brunetti FS, Gu G, Foti DP, et al. Cooperation between HMGA1, PDX-1, and MafA is Essential for Glucose-Induced Insulin Transcription in Pancreatic Beta Cells.

Front Endocrinol. Foti D, Chiefari E, Fedele M, Iuliano R, Brunetti L, Paonessa F, et al. Lack of the architectural factor HMGA1 causes insulin resistance and diabetes in human and mice. Nat Med. Chiefari E, Tanyolaç S, Paonessa F, Pullinger CR, Capula C, Iiritano S, et al. Functional variants of the HMGA1 gene and type 2 diabetes mellitus.

JAMA Chiefari E, Tanyolaç S, Iiritano S, Sciacqua A, Arcidiacono B, et al. A polymorphism of HMGA1 is associated with increased risk of metabolic syndrome and related components.

Sci Rep. Bustin M, Lehn DA, Landsman D. Structural features of the HMG chromosomal proteins and their genes.

Fusco A, Fedele M. Roles of HMGA proteins in cancer. Nat Rev Cancer — Leppek K, Das R, Barna M. Nat Rev Mol Cel Biol. Friedmann M, Holth LT, Zoghbi HY, Reeves R. Organization, inducible-expression, and chromosome localization of the human HMG-I Y nonhistone protein gene.

Nucleic Acids Res. Ogram SA, Reeves R. Differential regulation of a multipromoter gene. Cleynen I, Huysmans C, Sasazuki T, Shirasawa S, Van de Ven W, Peeters K.

Transcriptional control of the human high mobility group A1 gene: basal and oncogenic Ras-regulated expression. Wood LJ, Mukherjee M, Dolde CE, Xu Y, Maher JF, Bunton TE, et al. Zhong J, Liu C, Zhang QH, Chen L, Shen YY, Chen YJ, et al. TGF-β1 induces HMGA1 expression: The role of HMGA1 in thyroid cancer proliferation and invasion.

Chiefari E, Arcidiacono B, Possidente K, Iiritano S, Ventura V, et al. Transcriptional regulation of the HMGA1 gene by octamer-binding proteins Oct-1 and Oct PLoS ONE 8:e Mao L, Wertzler KJ, Maloney SC, Wang Z, Magnuson NS, Reeves R. HMGA1 levels influence mitochondrial function and mitochondrial DNA repair efficiency.

Mol Cell Biol — Xue W, Huang J, Chen H, Zhang Y, Zhu X, Li J, et al. Histone methyltransferase G9a modulates hepatic insulin signaling via regulating HMGA1.

Johnson KR, Lehn DA, Reeves R. Alternative processing of mRNAs encoding mammalian chromosomal high-mobility-group proteins HMG-I and HMG-Y. PubMed Abstract Google Scholar.

Huth JR, Bewley CA, Nissen MS, Evans JN, Reeves R, Gronenborn AM, et al. The solution structure of an HMG-I Y -DNA complex defines a new architectural minor groove binding motif. Nat Struct Biol. Colombo DF, Burger L, Baubec T, Schübeler D. Binding of high mobility group A proteins to the mammalian genome occurs as a function of AT-content.

PLoS Genet. Harrer M, Lührs H, Bustin M, Scheer U, Hock R. Dynamic interaction of HMGA1a proteins with chromatin. J Cell Sci. Reeves R, Edberg DD, Li Y. Architectural transcription factor HMGI Y promotes tumor progression and mesenchimal transition of human epithelial cells.

Mol Cell Biol Arnoldo L, Sgarra R, Chiefari E, Iiritano S, Arcidiacono B, Pegoraro S, et al. A novel mechanism of post-translational modulation of HMGA1 functions by the histone chaperone nucleophosmin. Sgarra R, Rustighi A, Tessari MA, Di Bernardo J, Altamura S, Fusco A, et al.

Nuclear phosphoproteins HMGA and their relationship with chromatin structure and cancer. FEBS Lett. Catez F, Yang H, Tracey KJ, Reeves R, Misteli T, Bustin M.

Network of dynamic interactions between histone H1 and high-mobility group proteins in chromatin. Borrmann L, Wilkening S, Bullerdiek J.

Oncogene — D'Angelo D, Esposito F, Fusco A. Epigenetic mechanisms leading to overexpression of HMGA proteins in human pituitary adenomas. Front Med. Fu X, Dong B, Tian Y, Lefebre P, Meng Z, Wang X, et al.

MicroRNAa regulates insulin sensitivity and metabolism of glucose and lipids. J Clin Invest. Chiefari E, Iiritano S, Paonessa F, Le Pera I, Arcidiacono B, Filocamo M, et al. Pseudogene-mediated posttranscriptional silencing of HMGA1 can result in insulin resistance and type 2 diabetes. Nat Commun.

Balakirev ES, Ayala FJ. Annu Rev Genet. Goncalves I, Duret L, Mouchiroud D. Nature and structure of human genes that generate retropseudogenes. Genome Res. Sakai H, Koyanagi KO, Imanishi T, Gojobori T. Frequent emergence and functional resurrection of processed pseudogenes in the human and mouse genomes.

Gene — De Martino M, Forzati F, Arra C, Fusco A, Esposito F. HMGA1-pseudogenes and cancer. Oncotarget — Zhang Q, Wang Y.

High mobility group proteins and their post-translational modifications. Sgarra R, Maurizio E, Zammitti S, Lo Sardo A, Giancotti V. Macroscopic differences in HMGA oncoproteins posttranslational modifications: C-terminal phosphorylation of HMGA2 affects its DNA binding properties.

J Proteome Res. Lund T, Laland SG. The metaphase specific phosphorylation of HMG I. Biochem Biophys Res Commun. Nissen MS, Langan TA, Reeves R.

Phosphorylation by cdc2 kinase modulates DNA binding activity of high mobility group I nonhistone chromatin protein. J Biol. Xiao DM, Pak JH, Wang X, Sato T, Huang FL, Chen HC, et al.

J Neurochem. Palvimo J, Linnala-Kankkunen A. Identification of sites on chromosomal protein HMG-I phosphorylated by casein kinase II. Maurizio E, Cravello L, Brady L, Spolaore B, Arnoldo L, Giancotti V, et al.

Conformational role for the C-terminal tail of the intrinsically disordered high mobility group A HMGA chromatin factors. Munshi N, Agalioti T, Lomvardas S, Merika M, Chen G, Thanos D. Coordination of a transcriptional switch by HMGI Y acetylation. Gain access to all of the material and topics, custom-made just for you.

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In addition, other effects such as preferential hydration of the products, lower charge density in the products, and less competing resonances in the products all contribute to the thermodynamically favorable hydrolysis of the reactants.

Thioesters such as Acetyl-SCoA are also included as they have the same negative ΔG 0 of hydrolysis as ATP, even though they lack an "anhydride" motif. Thioesters are destabilized compared to their hydrolysis products and in comparison to esters made with alcohol since the C-S bond is weaker.

Redox reactions: Everyone knows that redox reactions are thermodynamically favored if the oxidizing agent deployed is strong enough. The oxidation reactions of hydrocarbons, sugars, and fats by dioxygen are clearly exergonic we do call these combustion reactions after all.

What about redox reactions with less powerful oxidants? Are all these reactions as favored as combustion? Hardly so. Remember that in every redox reaction, an oxidizing and reducing agent react to form another oxidizing and reducing agent.

Consider the following reaction:. This reaction can go either way and is reversible. The above form is written in the favored direction in anaerobic metabolism when both Pyr and NADH levels are high. Although the ΔG 0 favors the oxidation of lactate, given the high concentration of Pyr and NADH, the reaction is driven in the opposite direction and proceeds as shown.

The best enzymes to regulate are those that catalyze the first committed step in the reaction pathway. These reactions often occur from key metabolic intermediates that are immediately before or proximal to branches in reaction pathways. In reality, metabolic regulation is more complex and is distributed to many steps in a reaction pathway in ways that might not be evident without details mathematical analyses.

We will discuss that in the next sections on metabolic control analysis. Fundamentals of Biochemistry Vol. II - Bioenergetics and Metabolism. jpg" ]. Search site Search Search. Go back to previous article.

Sign in. II - Bioenergetics and Metabolism Principles of Metabolic Regulation Changing the activity of a pre-existing enzyme The quickest way to modulate the activity of an enzyme is to alter the activity of an enzyme that already exists in the cell.

The list below, illustrated in the following figure, gives common ways to regulate enzyme activity Substrate availability : Substrates reactants bind to enzymes with a characteristic affinity characterized by a dissociation constant and a kinetic parameter called Km units of molarity.

If the actual concentration of a substrate in a cell is much less than the Km, the activity of the enzyme is very low. If the substrate concentration is much greater than Km, the enzyme's active site is saturated with substrate and the enzyme is maximally active.

Product inhibition : A product of an enzyme-catalyzed reaction often resembles a starting reactant, so it should be clear that the product should also bind to the activity site, albeit probably with lower affinity. Under conditions in which the product of a reaction is present in high concentration, it would be energetically advantageous to the cell if no more product was synthesized.

Product inhibition is hence commonly observed. Likewise, it is energetically advantageous to a cell if the end product of an entire pathway could likewise bind to the initial enzyme in the pathways and inhibit it, allowing the whole pathway to be inhibited.

This type of feedback inhibition is commonly observed. A quick look at biochemistry: carbohydrate metabolism. Clin Biochem. Desvergne B, Michalik L, Wahli W.

Transcriptional regulation of metabolism. Physiol Rev. Kitamura T. The role of FOXO1 in beta-cell failure and type 2 diabetes mellitus. Nature Rev Endocrinol. CrossRef Full Text Google Scholar.

Nakae J, Park B-C, Accili D. Insulin stimulates phosphorylation of the forkhead transcription factor FKHR on serine through a Wortmannin-sensitive pathway. J Biol Chem. Accili D, Arden KC. FoxOs at the crossroads of cellular metabolism, differentiation, and transformation.

Cell —6. Cleynen I, Van and de Ven WJ. The HMGA proteins: a myriad of functions Review. Int J Oncol. Reeves R, Beckerbauer L. Biochim Biophys Acta — Wisniewski JR, Schwanbeck.

Int J Mol Med. Sumter TF, Xian Huso T, Koo M, Chang YT, Almasri TN, et al. The high mobility group A1 HMGA1 transcriptome in cancer and development. Curr Mol Med. Sgarra R, Zammitti S, Lo Sardo A, Maurizio E, Arnoldo L, Pegoraro S, et al.

HMGA molecular network: from transcriptional regulation to chromatin remodeling. Sgarra R, Diana F, Rustighi A, Manfioletti G, Giancotti V.

Increase of HMGA1a protein methylation is a distinctive characteristic of leukaemic cells induced to undergo apoptosis.

Cell Death Differ. Diana F, Sgarra R, Manfioletti G, Rustighi A, Poletto D, Sciortino MT, et al. A link between apoptosis and degree of phosphorylation of high mobility group A1a protein in leukemic cells. Resar LM. The high mobility group A1 gene: transforming inflammatory signals into cancer?

Cancer Res. Foti D, Iuliano R, Chiefari E, Brunetti A. Mol Cell Biol. Iiritano S, Chiefari E, Ventura V, Arcidiacono B, Possidente K, Nocera A, et al.

Mol Endocrinol. Bianconcini A, Lupo A, Capone S, Quadro L, Monti M, Zurlo D, et al. Int J Biochem Cell Biol. Arcidiacono B, Iiritano S, Chiefari E, Brunetti FS, Gu G, Foti DP, et al.

Cooperation between HMGA1, PDX-1, and MafA is Essential for Glucose-Induced Insulin Transcription in Pancreatic Beta Cells. Front Endocrinol. Foti D, Chiefari E, Fedele M, Iuliano R, Brunetti L, Paonessa F, et al.

Lack of the architectural factor HMGA1 causes insulin resistance and diabetes in human and mice. Nat Med. Chiefari E, Tanyolaç S, Paonessa F, Pullinger CR, Capula C, Iiritano S, et al. Functional variants of the HMGA1 gene and type 2 diabetes mellitus.

JAMA Chiefari E, Tanyolaç S, Iiritano S, Sciacqua A, Arcidiacono B, et al. A polymorphism of HMGA1 is associated with increased risk of metabolic syndrome and related components. Sci Rep. Bustin M, Lehn DA, Landsman D. Structural features of the HMG chromosomal proteins and their genes.

Fusco A, Fedele M. Roles of HMGA proteins in cancer. Nat Rev Cancer — Leppek K, Das R, Barna M. Nat Rev Mol Cel Biol. Friedmann M, Holth LT, Zoghbi HY, Reeves R. Organization, inducible-expression, and chromosome localization of the human HMG-I Y nonhistone protein gene.

Nucleic Acids Res. Ogram SA, Reeves R. Differential regulation of a multipromoter gene. Cleynen I, Huysmans C, Sasazuki T, Shirasawa S, Van de Ven W, Peeters K. Transcriptional control of the human high mobility group A1 gene: basal and oncogenic Ras-regulated expression.

Wood LJ, Mukherjee M, Dolde CE, Xu Y, Maher JF, Bunton TE, et al. Zhong J, Liu C, Zhang QH, Chen L, Shen YY, Chen YJ, et al. TGF-β1 induces HMGA1 expression: The role of HMGA1 in thyroid cancer proliferation and invasion. Chiefari E, Arcidiacono B, Possidente K, Iiritano S, Ventura V, et al.

Transcriptional regulation of the HMGA1 gene by octamer-binding proteins Oct-1 and Oct PLoS ONE 8:e Mao L, Wertzler KJ, Maloney SC, Wang Z, Magnuson NS, Reeves R.

HMGA1 levels influence mitochondrial function and mitochondrial DNA repair efficiency. Mol Cell Biol — Xue W, Huang J, Chen H, Zhang Y, Zhu X, Li J, et al. Histone methyltransferase G9a modulates hepatic insulin signaling via regulating HMGA1.

Johnson KR, Lehn DA, Reeves R. Alternative processing of mRNAs encoding mammalian chromosomal high-mobility-group proteins HMG-I and HMG-Y. PubMed Abstract Google Scholar. Huth JR, Bewley CA, Nissen MS, Evans JN, Reeves R, Gronenborn AM, et al.

The solution structure of an HMG-I Y -DNA complex defines a new architectural minor groove binding motif. Nat Struct Biol. Colombo DF, Burger L, Baubec T, Schübeler D. Binding of high mobility group A proteins to the mammalian genome occurs as a function of AT-content.

PLoS Genet. Harrer M, Lührs H, Bustin M, Scheer U, Hock R. Dynamic interaction of HMGA1a proteins with chromatin. J Cell Sci. Reeves R, Edberg DD, Li Y. Architectural transcription factor HMGI Y promotes tumor progression and mesenchimal transition of human epithelial cells.

Mol Cell Biol Arnoldo L, Sgarra R, Chiefari E, Iiritano S, Arcidiacono B, Pegoraro S, et al. A novel mechanism of post-translational modulation of HMGA1 functions by the histone chaperone nucleophosmin.

Sgarra R, Rustighi A, Tessari MA, Di Bernardo J, Altamura S, Fusco A, et al. Nuclear phosphoproteins HMGA and their relationship with chromatin structure and cancer. FEBS Lett. Catez F, Yang H, Tracey KJ, Reeves R, Misteli T, Bustin M.

Network of dynamic interactions between histone H1 and high-mobility group proteins in chromatin. Borrmann L, Wilkening S, Bullerdiek J.

Oncogene — D'Angelo D, Esposito F, Fusco A. Epigenetic mechanisms leading to overexpression of HMGA proteins in human pituitary adenomas. Front Med. Fu X, Dong B, Tian Y, Lefebre P, Meng Z, Wang X, et al. MicroRNAa regulates insulin sensitivity and metabolism of glucose and lipids. J Clin Invest.

Chiefari E, Iiritano S, Paonessa F, Le Pera I, Arcidiacono B, Filocamo M, et al. Pseudogene-mediated posttranscriptional silencing of HMGA1 can result in insulin resistance and type 2 diabetes. Nat Commun. Balakirev ES, Ayala FJ.

Annu Rev Genet. Goncalves I, Duret L, Mouchiroud D. Nature and structure of human genes that generate retropseudogenes. Genome Res. Sakai H, Koyanagi KO, Imanishi T, Gojobori T. Frequent emergence and functional resurrection of processed pseudogenes in the human and mouse genomes.

Gene — De Martino M, Forzati F, Arra C, Fusco A, Esposito F. HMGA1-pseudogenes and cancer. Oncotarget — Zhang Q, Wang Y. High mobility group proteins and their post-translational modifications.

Sgarra R, Maurizio E, Zammitti S, Lo Sardo A, Giancotti V. Macroscopic differences in HMGA oncoproteins posttranslational modifications: C-terminal phosphorylation of HMGA2 affects its DNA binding properties. J Proteome Res. Lund T, Laland SG. The metaphase specific phosphorylation of HMG I. Biochem Biophys Res Commun.

Nissen MS, Langan TA, Reeves R. Phosphorylation by cdc2 kinase modulates DNA binding activity of high mobility group I nonhistone chromatin protein. J Biol. Xiao DM, Pak JH, Wang X, Sato T, Huang FL, Chen HC, et al. J Neurochem.

Palvimo J, Linnala-Kankkunen A. Identification of sites on chromosomal protein HMG-I phosphorylated by casein kinase II. Maurizio E, Cravello L, Brady L, Spolaore B, Arnoldo L, Giancotti V, et al.

Conformational role for the C-terminal tail of the intrinsically disordered high mobility group A HMGA chromatin factors. Munshi N, Agalioti T, Lomvardas S, Merika M, Chen G, Thanos D.

Coordination of a transcriptional switch by HMGI Y acetylation. Science —6. Sgarra R, Lee J, Tessari MA, Altamura S, Spolaore B, Giancotti V, et al. The AT-hook of the chromatin architectural transcription factor high mobility group A1a is arginine-methylated by protein arginine methyltransferase 6.

Sgarra R, Diana F, Bellarosa C, Dekleva V, Rustighi A, Toller M, et al. During apoptosis of tumor cells HMGA1a protein undergoes methylation: identification of the modification site by mass spectrometry.

Biochemistry — Fonfría-Subirós E, Acosta-Reyes F, Saperas N, Pous J, Subirana JA, Campos JL. Crystal structure of a complex of DNA with one AT-hook of HMGA1. PLoS ONE 7:e Chiappetta G, Avantaggiato V, Visconti R, Fedele M, Battista S, Trapasso F, et al.

High level expression of the HMGI Y gene during embryonic development. Yanagisawa BL, Resar LM. Hitting the bull's eye: targeting HMGA1 in cancer stem cells. Expert Rev Anticancer Ther. Fedele M, Fidanza V, Battista S, Pentimalli F, Klein-Szanto AJ, Visone R, et al.

Haploinsufficiency of the Hmga1 gene causes cardiac hypertrophy and myelolymphoproliferative disorders in mice. Cancer Res Arce-Cerezo A, Garcia M, Rodriguez-Nuevo A, Crosa-Bonell M, Enguiz N, Pero A, et al. HMGA1 overexpression in adipose tissue impairs adipogenesis and prevents diet-induced obesity and insulin resistance.

Brocher J, Vogel B, Hock R. HMGA1 down-regulation is crucial for chromatin composition and gene expression profile permitting myogenic differentiation. BMC Cell Biol. Sgarra R, Pegoraro S, Ros G, Penzo C, Chiefari E, Foti D, et al. High Mobility Group A HMGA proteins: molecular instigators of breast cancer onset and progression.

Greco M, Arcidiacono B, Chiefari E, Vitagliano T, Ciraco AG, Brunetti FS, et al. HMGA1 and MMP are overexpressed in human non-melanoma skin cancer. Anticancer Res. Pegoraro S, Ros G, Ciani Y, Sgarra R, Piazza S, Manfioletti G. A novel HMGA1-CCNE2-YAP axis regulates breast cancer aggressiveness. Pegoraro S, Ros G, Piazza S, Sommaggio R, Ciani Y, Rosato A, et al.

HMGA1 promotes metastatic processes in basal-like breast cancer regulating EMT and stemness. Maurizio E, Wiśniewski JR, Ciani Y, Amato A, Arnoldo L, Penzo C, et al. Translating proteomic into functional data: an High Mobility Group A1 HMGA1 proteomic signature has prognostic value in breast cancer.

Mol Cell Proteomics — Resmini G, Rizzo S, Franchin C, Zanin R, Penzo C, Pegoraro S, et al. HMGA1 regulates the plasminogen activation system in the secretome of breast cancer cells. Shah SN, Cope L, Poh W, Belton A, Roy S, Talbot CC, et al. HMGA1: a master regulator of tumor progression in triple-negative breast cancer cells.

Narita M, Narita M, Krizhanovsky V, Nunez S, Chicas A, Hearn SA, et al. A novel role for high-mobility group a proteins in cellular senescence and heterochromatin formation. Cell — Reeves R, Nissen MS. Cell cycle regulation and functions of HMGI Y.

Prog Cell Cycle Res. Google Scholar. Ozturk N, Singh I, Mehta A, Braun T, Barreto G. HMGA proteins as modulators of chromatin structure during transcriptional activation. Front Cell Dev Biol. Yie J, Merika M, Munshi N, Chen G, Thanos D.

The role of HMGI Y in the assembly and function of the IFN-beta enhanceosome. EMBO J. Grosschedl R. Higher-order nucleoprotein complexes in transcription: analogies with site-specific recombination.

Curr Opin Cell Biol. Merika M, Thanos D. Curr Opin Genet Dev. Sgarra R, Tessari MA, Di Bernardo J, Rustighi A, Zago P, Liberatori S, et al. Discovering high mobility group A molecular partners in tumour cells.

Proteomics — Sgarra R, Furlan C, Zammitti S, Lo Sardo A, Maurizio E, Di Bernardo J, et al. Interaction proteomics of the HMGA chromatin architectural factors.

Esposito F, Tornincasa M, Chieffi P, De Martino I, Pierantoni GM. Fusco A High-mobility group A1 proteins regulate pmediated transcription of the Bcl-2 gene. Costa V, Foti D, Paonessa F, Chiefari E, Palaia L, Brunetti G, Gulletta E, et al. The insulin receptor: a new anticancer target for peroxisome proliferator-activated receptor-gamma PPARgamma and thiazolidinedione-PPARgamma agonists.

Endocr Relat Cancer — Manabe T, Ohe K, Katayama T, Matsuzak i S, Yanagita T, Okuda H, et al. HMGA1a: sequence-specific RNA-binding factor causing sporadic Alzheimer's disease-linked exon skipping of presenilin-2 pre-mRNA. Genes Cells — Eilebrecht S, Benecke BJ, Benecke A.

RNA Biol. This enzyme catalyzes the phosphorylation of glucose , which helps to prepare the compound for cleavage in a later step. The presence of the negatively-charged phosphate in the molecule also prevents the sugar from leaving the cell.

When hexokinase is inhibited, glucose diffuses out of the cell and does not become a substrate for the respiration pathways in that tissue. The product of the hexokinase reaction is glucosephosphate, which accumulates when a later enzyme, phosphofructokinase , is inhibited.

Phosphofructokinase is the main enzyme controlled in glycolysis. Specifically, ATP binds an allosteric site on the enzyme to inhibit its activity.

An increase in citrate concentration can occur because of a blockage in the citric acid cycle. Fermentation, with its production of organic acids like lactic acid, frequently accounts for the increased acidity in a cell; however, the products of fermentation do not typically accumulate in cells.

The last step in glycolysis is catalyzed by pyruvate kinase. The pyruvate produced can proceed to be catabolized or converted into the amino acid alanine.

If no more energy is needed and alanine is in adequate supply, the enzyme is inhibited. Recall that fructose-1,6-bisphosphate is an intermediate in the first half of glycolysis.

The regulation of pyruvate kinase involves phosphorylation, resulting in a less-active enzyme. Dephosphorylation by a phosphatase reactivates it. Pyruvate kinase is also regulated by ATP a negative allosteric effect. If more energy is needed, more pyruvate will be converted into acetyl CoA through the action of pyruvate dehydrogenase.

If either acetyl groups or NADH accumulates, there is less need for the reaction and the rate decreases. Pyruvate dehydrogenase is also regulated by phosphorylation: a kinase phosphorylates it to form an inactive enzyme, and a phosphatase reactivates it. The kinase and the phosphatase are also regulated.

The gluconeogenesis involves the enzyme fructose 1,6-bisphosphatase that is regulated by the molecule citrate an intermediate in the citric acid cycle. Increased citrate will increase the activity of this enzyme. Gluconeogenesis needs ATP, so reduced ATP or increased AMP inhibits the enzyme and thus gluconeogenesis.

Type 2 diabetes mellitus. Diabetes and hyperglycemia. Fat metabolism deficiencies. Phosphofructokinase : any of a group of kinase enzymes that convert fructose phosphates to biphosphate. Glycolysis : the cellular metabolic pathway of the simple sugar glucose to yield pyruvic acid and ATP as an energy source.

Kinase : any of a group of enzymes that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific target molecules substrates ; the process is termed phosphorylation.

Glucose : a simple monosaccharide sugar with a molecular formula of C 6 H 12 O 6 ; it is a principal source of energy for cellular metabolism. Hexokinase: an enzyme that phosphorylates hexoses six-carbon sugars , forming hexose phosphate. Pyruvate: a biological molecule that consists of three carbon atoms and two functional groups — a carboxylate and a ketone group.

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