Comparative genomics guided discovery of two missing archaeal enzyme families involved in the biosynthesis of the pterin moiety of tetrahydromethanopterin and tetrahydrofolate

ACS Chem Biol. 2012 Nov 16;7(11):1807-16. doi: 10.1021/cb300342u. Epub 2012 Sep 7.

Abstract

C-1 carriers are essential cofactors in all domains of life, and in Archaea, these can be derivatives of tetrahydromethanopterin (H(4)-MPT) or tetrahydrofolate (H(4)-folate). Their synthesis requires 6-hydroxymethyl-7,8-dihydropterin diphosphate (6-HMDP) as the precursor, but the nature of pathways that lead to its formation were unknown until the recent discovery of the GTP cyclohydrolase IB/MptA family that catalyzes the first step, the conversion of GTP to dihydroneopterin 2',3'-cyclic phosphate or 7,8-dihydroneopterin triphosphate [El Yacoubi, B.; et al. (2006) J. Biol. Chem., 281, 37586-37593 and Grochowski, L. L.; et al. (2007) Biochemistry46, 6658-6667]. Using a combination of comparative genomics analyses, heterologous complementation tests, and in vitro assays, we show that the archaeal protein families COG2098 and COG1634 specify two of the missing 6-HMDP synthesis enzymes. Members of the COG2098 family catalyze the formation of 6-hydroxymethyl-7,8-dihydropterin from 7,8-dihydroneopterin, while members of the COG1634 family catalyze the formation of 6-HMDP from 6-hydroxymethyl-7,8-dihydropterin. The discovery of these missing genes solves a long-standing mystery and provides novel examples of convergent evolutions where proteins of dissimilar architectures perform the same biochemical function.

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

  • Archaea / enzymology*
  • Archaea / genetics*
  • Archaea / metabolism
  • Archaeal Proteins / genetics*
  • Archaeal Proteins / metabolism*
  • Genes, Archaeal
  • Genomics
  • Models, Molecular
  • Neopterin / analogs & derivatives
  • Neopterin / metabolism
  • Phylogeny
  • Pterins / metabolism*
  • Tetrahydrofolates / metabolism*

Substances

  • 6-hydroxymethyl-7,8-dihydropterin
  • Archaeal Proteins
  • Pterins
  • Tetrahydrofolates
  • dihydroneopterin triphosphate
  • 5,6,7,8-tetrahydrofolic acid
  • Neopterin
  • 5,6,7,8-tetrahydromethanopterin