What controls glycolysis in bloodstream form Trypanosoma brucei?
What controls glycolysis in bloodstream form Trypanosoma brucei?
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DOI：
10.1074/jbc.274.21.14551
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发表时间：
1999-05-21
影响因子：
4.8
通讯作者：
Westerhoff, HV
中科院分区：
文献类型：
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作者：
Bakker, BM;Michels, PAM;Westerhoff, HV
在实验确定的锥虫酶的动力学性质的基础上，解决的问题是哪一步限制糖酵解通量在血流形成的布鲁氏锥虫。似乎没有一个人回答；在生理范围内，葡萄糖转运体与醛缩酶（ALD）、甘油醛-3-磷酸脱氢酶（GAPBH）、磷酸甘油酸激酶（PGK）和甘油-3-磷酸脱氢酶（GDH）之间的控制发生了转移。通常被认为控制糖酵解的其他激酶几乎没有控制作用；ATP的利用也是如此。我们通过计算哪些步骤需要最少的抑制来实现对这些寄生虫糖酵解通量的一定抑制，从而确定了抗锥虫药物的潜在靶点。葡萄糖转运蛋白似乎是最有希望的靶标，其次是ALD、GDH、GAPDH和PGK。相比之下，红细胞中超过95%的PGK、GAPDH或ALD缺乏不会引起任何临床症状（Schuster， R.和Holzhutter， H.-G.）。(1995)毛皮。因此，抑制这些酶的药物的选择性可能比仅从它们的分子效应中预期的要高得多。相当出乎意料的是，锥虫似乎具有大量过剩的己糖激酶、磷酸果糖激酶和丙酮酸激酶，使这些“不可逆”的酶成为平庸的药物靶标。
On the basis of the experimentally determined kinetic properties of the trypanosomal enzymes, the question is addressed of which step limits the glycolytic flux in bloodstream form Trypanosoma brucei. There appeared to be no single answer; in the physiological range, control shifted between the glucose transporter on the one hand and aldolase (ALD), glyceraldehyde-3-phosphate dehydrogenase (GAPBH), phosphoglycerate kinase (PGK), and glycerol-3-phosphate dehydrogenase (GDH) on the other hand. The other kinases, which are often thought to control glycolysis, exerted little control; so did the utilization of ATP.We identified potential targets for anti-trypanosomal drugs by calculating which steps need the least inhibition to achieve a certain inhibition of the glycolytic flux in these parasites. The glucose transporter appeared to be the most promising target, followed by ALD, GDH, GAPDH, and PGK, By contrast, in erythrocytes more than 95% deficiencies of PGK, GAPDH, or ALD did not cause any clinical symptoms (Schuster, R. and Holzhutter, H.-G. (1995) fur. J. Biochem. 229, 403-418), Therefore, the selectivity of drugs inhibiting these enzymes may be much higher than expected from their molecular effects alone, Quite unexpectedly trypanosomes seem to possess a substantial overcapacity of hexokinase, phosphofructokinase, and pyruvate kinase, making these "irreversible" enzymes mediocre drug targets.