Metabolic engineering of lactate dehydrogenase rescues mice from acidosis.
Metabolic engineering of lactate dehydrogenase rescues mice from acidosis.
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DOI：
10.1038/srep05189
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发表时间：
2014-06-05
影响因子：
4.6
通讯作者：
Murthy N
中科院分区：
文献类型：
--
作者：
Acharya AP;Rafi M;Woods EC;Gardner AB;Murthy N
酸中毒每年导致数百万人死亡，因此非常需要使酸中毒患者的血液pH值正常化的策略。乳酸脱氢酶（LDH）途径具有治疗酸中毒的巨大潜力，因为它能够将质子和丙酮酸盐转化为乳酸盐，从而提高血液pH值，但由于没有基于药物的方法用于体内工程代谢途径，因此开发成为治疗方法一直具有挑战性。在这份报告中，我们证明了LDH途径的代谢通量可以用化合物5-氨基-2-羟甲基苯基硼酸（阿坝）进行工程化，该化合物结合乳酸盐并通过将丙酮酸盐转化为乳酸盐并增加NAD+/NADH比率来加速质子的消耗。我们在这里证明，阿坝可以拯救小鼠二甲双胍诱导的酸中毒，通过结合乳酸盐，并增加血液pH值从6.7到7.2和血液NAD+/NADH比5倍。阿坝是第一类可以代谢工程LDH途径的分子，并有可能对医学产生重大影响，因为大量患者患有酸中毒。
Acidosis causes millions of deaths each year and strategies for normalizing the blood pH in acidosis patients are greatly needed. The lactate dehydrogenase (LDH) pathway has great potential for treating acidosis due to its ability to convert protons and pyruvate into lactate and thereby raise blood pH, but has been challenging to develop into a therapy because there are no pharmaceutical-based approaches for engineering metabolic pathways in vivo. In this report we demonstrate that the metabolic flux of the LDH pathway can be engineered with the compound 5-amino-2-hydroxymethylphenyl boronic acid (ABA), which binds lactate and accelerates the consumption of protons by converting pyruvate to lactate and increasing the NAD+/NADH ratio. We demonstrate here that ABA can rescue mice from metformin induced acidosis, by binding lactate, and increasing the blood pH from 6.7 to 7.2 and the blood NAD+/NADH ratio by 5 fold. ABA is the first class of molecule that can metabolically engineer the LDH pathway and has the potential to have a significant impact on medicine, given the large number of patients that suffer from acidosis.
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