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Title: A family of metal-dependent phosphatases implicated in metabolite damage-control

Journal Article · · Nature Chemical Biology
 [1];  [2];  [3];  [4];  [3];  [3];  [3];  [3];  [3];  [1];  [1];  [1];  [1];  [5];  [1];  [4];  [3];  [3];  [1]
  1. Univ. of Florida, Gainesville, FL (United States)
  2. Brookhaven National Lab. (BNL), Upton, NY (United States)
  3. Univ. of Toronto, ON (Canada)
  4. Argonne National Lab. (ANL), Argonne, IL (United States)
  5. Univ. of California, Davis, CA (United States)
+ Show Author Affiliations

DUF89 family proteins occur widely in pro- and eukaryotes but their functions are unknown. Here we define three DUF89 subfamilies (I, II, and III), subfamily II being split into standalone proteins and proteins fused to pantothenate kinase (PanK). We demonstrated that DUF89 proteins have metaldependent phosphatase activity against reactive phosphoesters or their damaged forms, notably sugar phosphates (subfamilies II and III), phosphopantetheine and its S-sulfonate or sulfonate (subfamily II-PanK fusions), and nucleotides (subfamily I). Genetic and comparative genomic data strongly associated DUF89 genes with phosphoester metabolism. The crystal structure of the yeast (Saccharomyces cerevisiae) subfamily III protein YMR027W revealed a novel phosphatase active site with fructose 6-phosphate and Mg2+ bound near conserved signature residues Asp254 and Asn255 that are critical for activity. These findings indicate that DUF89 proteins are previously unrecognized hydrolases whose characteristic in vivo function is to limit potentially harmful buildups of normal or damaged phosphometabolites.

Research Organization:
Brookhaven National Laboratory (BNL), Upton, NY (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES)
Grant/Contract Number:
SC00112704
OSTI ID:
1341633
Report Number(s):
BNL-112717-2016-JA
Journal Information:
Nature Chemical Biology, Vol. 12, Issue 8; ISSN 1552-4450
Publisher:
Nature Publishing GroupCopyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 34 works
Citation information provided by
Web of Science

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Cited By (9)

Inborn errors of coenzyme A metabolism and neurodegeneration journal January 2019
Human pantothenate kinase 4 is a pseudo‐pantothenate kinase journal April 2019
Inborn errors of coenzyme A metabolism and neurodegeneration journal May 2018
Longevity of major coenzymes allows minimal de novo synthesis in microorganisms journal May 2017
Gene Graphics: a genomic neighborhood data visualization web application journal December 2017
Diadenosine tetraphosphate (Ap4A) - an E. coli alarmone or a damage metabolite? journal June 2017
Enzyme promiscuity, metabolite damage, and metabolite damage control systems of the tricarboxylic acid cycle journal March 2020
Systematic identification and analysis of frequent gene fusion events in metabolic pathways journal June 2016
Vnn1 pantetheinase limits the Warburg effect and sarcoma growth by rescuing mitochondrial activity journal July 2018

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