Comparative genomics of NAD(P) biosynthesis and novel antibiotic drug targets.
NAD(P) is an indispensable cofactor for all organisms and its biosynthetic pathways are proposed as promising novel antibiotics targets against pathogens such as Mycobacterium tuberculosis. Six NAD(P) biosynthetic pathways were reconstructed by comparative genomics: de novo pathway (Asp), de novo pathway (Try), NmR pathway I (RNK-dependent), NmR pathway II (RNK-independent), Niacin salvage, and Niacin recycling. Three enzymes pivotal to the key reactions of NAD(P) biosynthesis are shared by almost all organisms, that is, NMN/NaMN adenylyltransferase (NMN/NaMNAT), NAD synthetase (NADS), and NAD kinase (NADK). They might serve as ideal broad spectrum antibiotic targets. Studies in M. tuberculosis have in part tested such hypothesis. Three regulatory factors NadR, NiaR, and NrtR, which regulate NAD biosynthesis, have been identified. M. tuberculosis NAD(P) metabolism and regulation thereof, potential drug targets and drug development are summarized in this paper.
Bi
Jicai
J
Institute of Modern Biopharmaceuticals, School of Life Sciences, Southwest University, Chongqing, China.
Wang
Honghai
H
Xie
Jianping
J
D019732:Amide Synthases / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D015195:Drug Design; D023281:Genomics; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics / Q000472:pathogenicity; D009249:NADP / Q000096:biosynthesis*; D009537:Nicotinamide Mononucleotide / Q000737:chemistry / Q000378:metabolism; D009612:Nicotinamide-Nucleotide Adenylyltransferase / Q000235:genetics / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D014376:Tuberculosis / Q000378:metabolism
D000900:Anti-Bacterial Agents; D009537:Nicotinamide Mononucleotide; D009249:NADP; D017853:Phosphotransferases (Alcohol Group Acceptor); C021844:NAD kinase; D009612:Nicotinamide-Nucleotide Adenylyltransferase; C038480:nicotinic acid mononucleotide adenylyltransferase; D019732:Amide Synthases; C038479:NAD+ synthase