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

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 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 COG 1634 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 example's of convergent evolutions Where Proteins of dissimilar architectures perform the same biochemical function.