Increased glutarate production by blocking the glutaryl-CoA dehydrogenation pathway and a catabolic pathway involving L-2-hydroxyglutarate

Nat Commun. 2018 May 29;9(1):2114. doi: 10.1038/s41467-018-04513-0.

Abstract

Glutarate is a five carbon platform chemical produced during the catabolism of L-lysine. It is known that it can be catabolized through the glutaryl-CoA dehydrogenation pathway. Here, we discover that Pseudomonas putida KT2440 has an additional glutarate catabolic pathway involving L-2-hydroxyglutarate (L-2-HG), an abnormal metabolite produced from 2-ketoglutarate (2-KG). In this pathway, CsiD, a Fe2+/2-KG-dependent glutarate hydroxylase, is capable of converting glutarate into L-2-HG, and LhgO, an L-2-HG oxidase, can catalyze L-2-HG into 2-KG. We construct a recombinant strain that lacks both glutarate catabolic pathways. It can produce glutarate from L-lysine with a yield of 0.85 mol glutarate/mol L-lysine. Thus, L-2-HG anabolism and catabolism is a metabolic alternative to the glutaryl-CoA dehydrogenation pathway in P. putida KT2440; L-lysine can be both ketogenic and glucogenic.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyl Coenzyme A / metabolism
  • Dioxygenases / metabolism*
  • Glutarates / metabolism*
  • Glutaryl-CoA Dehydrogenase / antagonists & inhibitors
  • Glutaryl-CoA Dehydrogenase / genetics*
  • Glutaryl-CoA Dehydrogenase / metabolism*
  • Glyoxylates / metabolism
  • L-Lactate Dehydrogenase / metabolism
  • Lysine / metabolism
  • Malate Dehydrogenase / metabolism
  • Mixed Function Oxygenases / metabolism*
  • Pseudomonas putida / enzymology
  • Pseudomonas putida / genetics
  • Pseudomonas putida / metabolism*

Substances

  • Acyl Coenzyme A
  • Glutarates
  • Glyoxylates
  • alpha-hydroxyglutarate
  • glutaryl-coenzyme A
  • Mixed Function Oxygenases
  • L-Lactate Dehydrogenase
  • Malate Dehydrogenase
  • Dioxygenases
  • Glutaryl-CoA Dehydrogenase
  • glyoxylic acid
  • Lysine