title: Sequence-motif detection of NAD(P)-binding proteins: discovery of a unique antibacterial drug target.
abstract: Many enzymes use nicotinamide adenine dinucleotide or nicotinamide adenine dinucleotide phosphate (NAD(P)) as essential coenzymes. These enzymes often do not share significant sequence identity and cannot be easily detected by sequence homology. Previously, we determined all distinct locally conserved pyrophosphate-binding structures (3d motifs) from NAD(P)-bound protein structures, from which 1d sequence motifs were derived. Here, we aim to establish the precision of these 3d and 1d motifs to annotate NAD(P)-binding proteins. We show that the pyrophosphate-binding 3d motifs are characteristic of NAD(P)-binding proteins, as they are rarely found in nonNAD(P)-binding proteins. Furthermore, several 1d motifs could distinguish between proteins that bind only NAD and those that bind only NADP. They could also distinguish between NAD(P)-binding proteins from nonNAD(P)-binding ones. Interestingly, one of the pyrophosphate-binding 3d and corresponding 1d motifs was found only in enoyl-acyl carrier protein reductases, which are enzymes essential for bacterial fatty acid biosynthesis. This unique 3d motif serves as an attractive novel drug target, as it is conserved across many bacterial species and is not found in human proteins.
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.
authors.forename: Yun Hao
authors.initials: YH
authors.lastname: Hua
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.
authors.forename: Chih Yuan
authors.initials: CY
authors.lastname: Wu
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.
authors.forename: Karen
authors.initials: K
authors.lastname: Sargsyan
authors.affiliation: 1] Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan [2] Department of Chemistry, National Tsing Hua University, Hsinchu 300, Taiwan.
authors.forename: Carmay
authors.initials: C
authors.lastname: Lim
mesh_terms: D020816:Amino Acid Motifs / Q000187:drug effects / Q000235:genetics*; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000627:therapeutic use; D001419:Bacteria / Q000187:drug effects / Q000201:enzymology; D002352:Carrier Proteins / Q000235:genetics*; D016503:Drug Delivery Systems; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / Q000235:genetics; D006801:Humans; D009243:NAD / Q000235:genetics / Q000378:metabolism*; D009249:NADP / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics
chemical_list: D000900:Anti-Bacterial Agents; D002352:Carrier Proteins; D009243:NAD; D009249:NADP; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)