title: Metabolic engineering of lactate dehydrogenase rescues mice from acidosis.
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.
authors.affiliation: 306 Stanley Hall, Department of Bioengineering, University of California, Berkeley, California 94720.
authors.forename: Abhinav P
authors.initials: AP
authors.lastname: Acharya
authors.affiliation: 306 Stanley Hall, Department of Bioengineering, University of California, Berkeley, California 94720.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Rafi
authors.affiliation: 306 Stanley Hall, Department of Bioengineering, University of California, Berkeley, California 94720.
authors.forename: Elliot C
authors.initials: EC
authors.lastname: Woods
authors.affiliation: 306 Stanley Hall, Department of Bioengineering, University of California, Berkeley, California 94720.
authors.forename: Austin B
authors.initials: AB
authors.lastname: Gardner
authors.affiliation: 306 Stanley Hall, Department of Bioengineering, University of California, Berkeley, California 94720.
authors.forename: Niren
authors.initials: N
authors.lastname: Murthy
mesh_terms: D000138:Acidosis / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D000818:Animals; D001897:Boronic Acids / Q000494:pharmacology; D002478:Cells, Cultured; D005260:Female; D007004:Hypoglycemic Agents / Q000633:toxicity; D007700:Kinetics; D007770:L-Lactate Dehydrogenase / Q000378:metabolism*; D019344:Lactic Acid / Q000378:metabolism*; D060847:Metabolic Engineering; D053858:Metabolic Networks and Pathways; D008687:Metformin / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D019289:Pyruvic Acid / Q000378:metabolism*
chemical_list: D001897:Boronic Acids; D007004:Hypoglycemic Agents; D019344:Lactic Acid; D019289:Pyruvic Acid; D008687:Metformin; D007770:L-Lactate Dehydrogenase