title: Evolution of the nitric oxide synthase family in metazoans.
abstract: Nitric oxide (NO) is essential to many physiological functions and operates in several signaling pathways. It is not understood how and when the different isoforms of nitric oxide synthase (NOS), the enzyme responsible for NO production, evolved in metazoans. This study investigates the number and structure of metazoan NOS enzymes by genome data mining and direct cloning of Nos genes from the lamprey. In total, 181 NOS proteins are analyzed from 33 invertebrate and 63 vertebrate species. Comparisons among protein and gene structures, combined with phylogenetic and syntenic studies, provide novel insights into how NOS isoforms arose and diverged. Protein domains and gene organization--that is, intron positions and phases--of animal NOS are remarkably conserved across all lineages, even in fast-evolving species. Phylogenetic and syntenic analyses support the view that a proto-NOS isoform was recurrently duplicated in different lineages, acquiring new structural configurations through gains and losses of protein motifs. We propose that in vertebrates a first duplication took place after the agnathan-gnathostome split followed by a paralog loss. A second duplication occurred during early tetrapod evolution, giving rise to the three isoforms--I, II, and III--in current mammals. Overall, NOS family evolution was the result of multiple gene and genome duplication events together with changes in protein architecture.
authors.affiliation: Australian Institute of Marine Science, Townsville, Queensland, Australia.
authors.forename: Nikos
authors.initials: N
authors.lastname: Andreakis
authors.forename: Salvatore
authors.initials: S
authors.lastname: D'Aniello
authors.forename: Ricard
authors.initials: R
authors.lastname: Albalat
authors.forename: Francesco Paolo
authors.initials: FP
authors.lastname: Patti
authors.forename: Jordi
authors.initials: J
authors.lastname: Garcia-Fernàndez
authors.forename: Gabriele
authors.initials: G
authors.lastname: Procaccini
authors.forename: Paolo
authors.initials: P
authors.lastname: Sordino
authors.forename: Anna
authors.initials: A
authors.lastname: Palumbo
mesh_terms: D000818:Animals; D005075:Biological Evolution; D030541:Databases, Genetic; D004795:Enzyme Stability; D019143:Evolution, Molecular; D006801:Humans; D007438:Introns; D007527:Isoenzymes / Q000145:classification / Q000235:genetics*; D007798:Lampreys / Q000235:genetics* / Q000378:metabolism*; D016013:Likelihood Functions; D008969:Molecular Sequence Data; D005810:Multigene Family; D019001:Nitric Oxide Synthase / Q000145:classification / Q000235:genetics*; D010802:Phylogeny; D026801:Synteny
chemical_list: D007527:Isoenzymes; D019001:Nitric Oxide Synthase