Metabolite Damage and Damage Control in a Minimal Genome

Authors

Drago Haas, University of Florida
Antje M. Thamm, University of Florida
Jiayi Sun, University of Florida
Lili Huang, University of Florida Institute of Food and Agricultural Sciences
Lijie Sun, J. Craig Venter Institute
Guillaume A.W. Beaudoin, University of Florida
Kim S. Wise, J. Craig Venter Institute
Claudia Lerma-Ortiz, University of Florida
Steven D. Bruner, University of Florida
Marian Breuer, Universiteit Maastricht
Zaida Luthey-Schulten, University of Illinois Urbana-Champaign
Jiusheng Lin, University of Nebraska - LincolnFollow
Mark A. Wilson, Department of BiochemistryFollow
Greg Brown, University of Toronto
Alexander F. Yakunin, University of Toronto
Inna Kurilyak, University of California, Davis
Jacob Folz, University of California, Davis
Oliver Fiehn, University of California, Davis
John I. Glass, J. Craig Venter Institute
Andrew D. Hanson, University of Florida
Christopher S. Henry, Argonne National LaboratoryFollow
Valérie de Crécy-Lagard, University of FloridaFollow

Document Type

Article

Date of this Version

8-1-2022

Citation

MBio July/August 2022 Volume 13 Issue 4 doi:10.1128/mbio.01630-22

Comments

Copyright © 2022 Haas et al. This is an openaccess article distributed under the terms of the Creative Commons Attribution 4.0 International license.

Abstract

Analysis of the genes retained in the minimized Mycoplasma JCVI-Syn3A genome established that systems that repair or preempt metabolite damage are essential to life. Several genes known to have such functions were identified and experimentally validated, including 5-formyltetrahydrofolate cycloligase, coenzyme A (CoA) disulfide reductase, and certain hydrolases. Furthermore, we discovered that an enigmatic YqeK hydrolase domain fused to NadD has a novel proofreading function in NAD synthesis and could double as a MutT-like sanitizing enzyme for the nucleotide pool. Finally, we combined metabolomics and cheminformatics approaches to extend the core metabolic map of JCVI-Syn3A to include promiscuous enzymatic reactions and spontaneous side reactions. This extension revealed that several key metabolite damage control systems remain to be identified in JCVI-Syn3A, such as that for methylglyoxal. IMPORTANCE Metabolite damage and repair mechanisms are being increasingly recognized. We present here compelling genetic and biochemical evidence for the universal importance of these mechanisms by demonstrating that stripping a genome down to its barest essentials leaves metabolite damage control systems in place. Furthermore, our metabolomic and cheminformatic results point to the existence of a network of metabolite damage and damage control reactions that extends far beyond the corners of it that have been characterized so far. In sum, there can be little room left to doubt that metabolite damage and the systems that counter it are mainstream metabolic processes that cannot be separated from life itself.