title: Comparative genomics guided discovery of two missing archaeal enzyme families involved in the biosynthesis of the pterin moiety of tetrahydromethanopterin and tetrahydrofolate.
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.
authors.affiliation: Department of Microbiology and Department of Microbiology and Cell Science, University of Florida, P.O. Box 110700, Gainesville, Florida 32611-0700, United States. vcrecy@ufl.edu
authors.forename: Valérie
authors.initials: V
authors.lastname: de Crécy-Lagard
authors.forename: Gabriela
authors.initials: G
authors.lastname: Phillips
authors.forename: Laura L
authors.initials: LL
authors.lastname: Grochowski
authors.forename: Basma
authors.initials: B
authors.lastname: El Yacoubi
authors.forename: Francis
authors.initials: F
authors.lastname: Jenney
authors.forename: Michael W W
authors.initials: MW
authors.lastname: Adams
authors.forename: Alexey G
authors.initials: AG
authors.lastname: Murzin
authors.forename: Robert H
authors.initials: RH
authors.lastname: White
mesh_terms: D001105:Archaea / Q000201:enzymology* / Q000235:genetics* / Q000378:metabolism; D019843:Archaeal Proteins / Q000235:genetics* / Q000378:metabolism*; D019766:Genes, Archaeal; D023281:Genomics; D008958:Models, Molecular; D019798:Neopterin / Q000031:analogs & derivatives / Q000378:metabolism; D010802:Phylogeny; D011622:Pterins / Q000378:metabolism*; D013763:Tetrahydrofolates / Q000378:metabolism*
chemical_list: C492818:6-hydroxymethyl-7,8-dihydropterin; D019843:Archaeal Proteins; D011622:Pterins; D013763:Tetrahydrofolates; C013490:dihydroneopterin triphosphate; C030371:5,6,7,8-tetrahydrofolic acid; D019798:Neopterin; C042416:5,6,7,8-tetrahydromethanopterin