Dead enzymes in the aldehyde dehydrogenase gene family: role in drug metabolism and toxicology

Expert Opin Drug Metab Toxicol. 2015;11(12):1839-47. doi: 10.1517/17425255.2016.1108406. Epub 2015 Nov 11.

Abstract

Introduction: Dead enzymes are gene products (proteins) that lack key residues required for catalytic activity. In the pre-genome era, dead enzymes were thought to occur only rarely. However, they now have been shown to represent upwards of 10% of the total enzyme population in many families. The aldehyde dehydrogenase (ALDH) gene family encodes proteins that, depending on the isozyme, may be either catalytically-active or -inactive. Importantly, several ALDHs exhibit biological activities independent of their catalytic activity. For many of these, the physiological and pathophysiological functions remain to be established.

Areas covered: This article reviews the non-enzymatic functions of the ALDH superfamily. In addition, a search for additional non-catalytic ALDH records is undertaken. Our computational analyses reveal that there are currently 182 protein records (divided into 19 groups) that meet the criteria for dead enzymes.

Expert opinion: Dead enzymes have the potential to exert biological actions through protein-protein interaction and allosteric modulation of the activity of an active enzyme. In addition, a dead enzyme may also influence availability of substrate for other active enzymes by sequestering substrate, and/or anchoring the substrate to a particular subcellular space. A large number of putatively non-catalytic ALDH proteins exist that warrant further study.

Keywords: aldehyde dehydrogenase; computational analysis; dead enzymes.

Publication types

  • Review

MeSH terms

  • Aldehyde Dehydrogenase / genetics*
  • Aldehyde Dehydrogenase / metabolism
  • Allosteric Regulation / physiology
  • Animals
  • Catalysis
  • Drug-Related Side Effects and Adverse Reactions / genetics*
  • Humans
  • Isoenzymes
  • Pharmaceutical Preparations / metabolism*

Substances

  • Isoenzymes
  • Pharmaceutical Preparations
  • Aldehyde Dehydrogenase