Nutrient and hormonal regulation of pyruvate kinase gene expression

Abstract

Mammalian pyruvate kinase (PK), a key glycolytic enzyme, has two genes named PKL and PKM, which produce the L- and R-type isoenzymes by means of alternative promoters, and the M1-and M2-types by mutually exclusive alternative splicing respectively. The expression of these genes is tissue-specific and under developmental, dietary and hormonal control. The L-type isoenzyme (L-PK) gene contains multiple regulatory elements necessary for regulation in the 5' flanking region, up to position -170. Both L-II and L-III elements are required for stimulation of L-PK gene transcription by carbohydrates such as glucose and fructose, although the L-III element is itself responsive to carbohydrates. The L-II element is also responsible for the gene regulation by polyunsaturated fatty acids. Nuclear factor-1 proteins and hepatocyte nuclear factor 4, which bind to the L-II element, may also be involved in carbohydrate and polyunsaturated fatty acid regulation of the L-PK gene respectively. However, the L-III-element-binding protein that is involved in carbohydrate regulation remains to be clarified, although involvement by an upstream stimulating factor has been proposed. Available evidence suggests that the carbohydrate signalling pathway to the L-PK gene includes a glucose metabolite, possibly glucose 6-phosphate or xylulose 5-phosphate, as well as phosphorylation and dephosphorylation mechanisms. In addition, at least five regulatory elements have been identified in the 5' flanking region of the PKM gene up to position -279. Sp1-family proteins bind to two proximal elements, but the binding of proteins to other elements have not yet been clarified. Glucose may stimulate the transcription of the PKM gene via hexosamine derivatives. Sp1 may be involved in this regulation via its dephosphorylation, although the carbohydrate response element has not been determined precisely in the PKM gene. Thus glucose stimulates transcription of the PKM gene by the mechanism which is probably different from the L-PK gene.

The Synergistic Effect of Dexamethasone and All-trans-retinoic Acid on Hepatic Phosphoenolpyruvate Carboxykinase Gene Expression Involves the Coactivator p300

“…Examples include the tyrosine aminotransferase, fatty-acid synthase, L-type pyruvate kinase, insulin-like growth factor-binding proteins, and the glucose 6-phosphate catalytic subunit genes (32)(33)(34)(35)(36)(37). We have used the phrase "metabolic control domain" (MCD) to describe an array of DNA elements and associated transcription factors that provide an integrated response to a variety of signals (2,15).…”

Skeletal muscle proteome and meat quality of broiler chickens subjected to gas stunning prior slaughter or slaughtered without stunning

“…Other than muscle type (M-isozyme), pyruvate kinase also exists in different isoforms in the liver and erythrocyte. Similar to the other catalyst enzymes involved in the glycolysis metabolic pathway, the expression of pyruvate kinase is also dependent on the level of supply substrates such as PEP, fructose 1, 6 bisphosphate and ATP (Yamada & Noguchi, 1999). Low levels of substrate PEP and fructose 1:6 bisphosphate will switch to low production of pyruvate kinase while ATP molecules posed as negative allosteric inhibitor.…”

“…Low levels of substrate PEP and fructose 1:6 bisphosphate will switch to low production of pyruvate kinase while ATP molecules posed as negative allosteric inhibitor. Besides being regulated by concentration of substrates, the up-regulation of pyruvate kinase has also been associated with increased levels of adrenaline and insulin (Yamada & Noguchi, 1999). Hence, the physiological discomfort and stress by the gas stunning could be responsible for the higher expression of pyruvate kinase.…”

Nuclear Factor 1 Family Members Interact with Hepatocyte Nuclear Factor 1α to Synergistically Activate L-type Pyruvate Kinase Gene Transcription

“…They are produced from two genes, PKL and PKM, by alternative use of two promoters and mutually exclusive alternative splicing, respectively (2)(3)(4). The L-type isozyme (L-PK) is expressed in a tissue-specific manner; this form is expressed primarily in hepatic parenchymal cells and is also present in pancreatic ␤ cells, kidney, and small intestine (1). Hepatic L-PK gene expression is also transcriptionally controlled positively by glucose in the presence of insulin and negatively by polyunsaturated fatty acids or glucagon via cyclic AMP (5)(6)(7)(8).…”