Assignment of function to a domain of unknown function: DUF1537 is a new kinase family in catabolic pathways for acid sugars

Proc Natl Acad Sci U S A. 2016 Jul 19;113(29):E4161-9. doi: 10.1073/pnas.1605546113. Epub 2016 Jul 11.


Using a large-scale "genomic enzymology" approach, we (i) assigned novel ATP-dependent four-carbon acid sugar kinase functions to members of the DUF1537 protein family (domain of unknown function; Pfam families PF07005 and PF17042) and (ii) discovered novel catabolic pathways for d-threonate, l-threonate, and d-erythronate. The experimentally determined ligand specificities of several solute binding proteins (SBPs) for TRAP (tripartite ATP-independent permease) transporters for four-carbon acids, including d-erythronate and l-erythronate, were used to constrain the substrates for the catabolic pathways that degrade the SBP ligands to intermediates in central carbon metabolism. Sequence similarity networks and genome neighborhood networks were used to identify the enzyme components of the pathways. Conserved genome neighborhoods encoded SBPs as well as permease components of the TRAP transporters, members of the DUF1537 family, and a member of the 4-hydroxy-l-threonine 4-phosphate dehydrogenase (PdxA) oxidative decarboxylase, class II aldolase, or ribulose 1,5-bisphosphate carboxylase/oxygenase, large subunit (RuBisCO) superfamily. Because the characterized substrates of members of the PdxA, class II aldolase, and RuBisCO superfamilies are phosphorylated, we postulated that the members of the DUF1537 family are novel ATP-dependent kinases that participate in catabolic pathways for four-carbon acid sugars. We determined that (i) the DUF1537/PdxA pair participates in a pathway for the conversion of d-threonate to dihydroxyacetone phosphate and CO2 and (ii) the DUF1537/class II aldolase pair participates in pathways for the conversion of d-erythronate and l-threonate (epimers at carbon-3) to dihydroxyacetone phosphate and CO2 The physiological importance of these pathways was demonstrated in vivo by phenotypic and genetic analyses.

Keywords: DUF1537; conserved genome neighborhoods; four-carbon acid sugars; genomic enzymology; kinase.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Bacteria / enzymology
  • Bacteria / isolation & purification
  • Bacterial Proteins / chemistry*
  • Bacterial Proteins / metabolism*
  • Butyrates / metabolism
  • Fructose-Bisphosphate Aldolase / metabolism
  • Oxidoreductases / metabolism
  • Phosphates / metabolism
  • Protein Domains
  • Protein Kinases / chemistry*
  • Protein Kinases / metabolism*


  • Bacterial Proteins
  • Butyrates
  • Phosphates
  • erythronic acid
  • Oxidoreductases
  • Protein Kinases
  • Fructose-Bisphosphate Aldolase
  • threonic acid

Associated data

  • PDB/4XFM
  • PDB/4XFR
  • PDB/4XG0
  • PDB/4XGJ
  • PDB/5DMH