Metabolic engineering of lactate dehydrogenase rescues mice from acidosis

Abhinav P. Acharya, Mohammad Rafi, Elliot C. Woods, Austin B. Gardner, Niren Murthy

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number5189
JournalScientific reports
Volume4
DOIs
StatePublished - Jun 5 2014
Externally publishedYes

ASJC Scopus subject areas

  • General

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