Comparative Genomics Guided Discovery of Two Missing Archaeal Enzyme Families Involved in the Biosynthesis of the Pterin Moiety of Tetrahydromethanopterin and Tetrahydrofolate

• Published in: ACS chemical biology 2012-11, Vol.7 (11), p.1807-1816
• Main Authors: Crécy-Lagard, Valérie de, Phillips, Gabriela, Grochowski, Laura L, Yacoubi, Basma El, Jenney, Francis, Adams, Michael W. W, Murzin, Alexey G, White, Robert H
• Format: Article
• Language: English
• Subjects: Archaea - enzymology; Archaea - genetics; Archaea - metabolism; Archaeal Proteins - genetics; Archaeal Proteins - metabolism; Genes, Archaeal; Genomics; Letters; Models, Molecular; Neopterin - analogs & derivatives; Neopterin - metabolism; Phylogeny; Pterins - metabolism; Tetrahydrofolates - metabolism
• ISSN: 1554-8929; 1554-8937
• DOI: 10.1021/cb300342u

C-1 carriers are essential cofactors in all domains of life, and in Archaea, these can be derivatives of tetrahydromethanopterin (H4-MPT) or tetrahydrofolate (H4-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) Biochemistry 46, 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.