Acharya Abhinav P, Rafi Mohammad, Woods Elliot C, Gardner Austin B, Murthy Niren
306 Stanley Hall, Department of Bioengineering, University of California, Berkeley, California 94720.
Sci Rep. 2014 Jun 5;4:5189. doi: 10.1038/srep05189.
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.
酸中毒每年导致数百万人死亡，因此迫切需要使酸中毒患者血液pH值正常化的策略。乳酸脱氢酶（LDH）途径因其能够将质子和丙酮酸转化为乳酸从而提高血液pH值，在治疗酸中毒方面具有巨大潜力，但由于缺乏在体内改造代谢途径的基于药物的方法，将其开发成一种疗法一直具有挑战性。在本报告中，我们证明了可以用化合物5-氨基-2-羟甲基苯硼酸（ABA）来改造LDH途径的代谢通量，该化合物结合乳酸，并通过将丙酮酸转化为乳酸和增加NAD(+)/NADH比率来加速质子的消耗。我们在此证明，ABA可以通过结合乳酸，将血液pH值从6.7提高到7.2，并将血液NAD(+)/NADH比率提高5倍，从而使小鼠从二甲双胍诱导的酸中毒中获救。ABA是第一类能够对LDH途径进行代谢工程改造的分子，鉴于大量患者患有酸中毒，它有可能对医学产生重大影响。
