Yamada K, Noguchi T
Department of Biochemistry, Fukui Medical University, Shimoaizuki, Matsuoka, Fukui 910-1193, Japan.
Biochem J. 1999 Jan 1;337 ( Pt 1)(Pt 1):1-11.
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.
哺乳动物丙酮酸激酶（PK）是糖酵解的关键酶，有两个基因，即PKL和PKM，它们通过不同的启动子分别产生L型和R型同工酶，通过相互排斥的可变剪接分别产生M1型和M2型同工酶。这些基因的表达具有组织特异性，并受发育、饮食和激素的调控。L型同工酶（L-PK）基因在其5'侧翼区（至-170位）含有多个调控所需的元件。L-II和L-III元件都是葡萄糖和果糖等碳水化合物刺激L-PK基因转录所必需的，尽管L-III元件自身对碳水化合物有反应。L-II元件也负责多不饱和脂肪酸对该基因的调控。与L-II元件结合的核因子-1蛋白和肝细胞核因子4可能分别参与L-PK基因的碳水化合物和多不饱和脂肪酸调控。然而，尽管有人提出上游刺激因子参与其中，但参与碳水化合物调控的L-III元件结合蛋白仍有待阐明。现有证据表明，通向L-PK基因的碳水化合物信号通路包括一种葡萄糖代谢物，可能是6-磷酸葡萄糖或5-磷酸木酮糖，以及磷酸化和去磷酸化机制。此外，在PKM基因的5'侧翼区（至-279位）已鉴定出至少五个调控元件。Sp1家族蛋白与两个近端元件结合，但其他元件与蛋白的结合情况尚未阐明。葡萄糖可能通过己糖胺衍生物刺激PKM基因的转录。Sp1可能通过其去磷酸化参与这一调控，尽管PKM基因中的碳水化合物反应元件尚未精确确定。因此，葡萄糖通过可能与L-PK基因不同的机制刺激PKM基因的转录。
