7XGL

Quinolinate Phosphoribosyl Transferase (QAPRTase) from Streptomyces pyridomyceticus NRRL B-2517 in Apo form

Summary for 7XGL

• Entry DOI: 10.2210/pdb7xgl/pdb
• Descriptor: Quinolinate Phosphoribosyl Transferase, SULFATE ION, GLYCEROL, ... (7 entities in total)
• Functional Keywords: nicotinamide adenine dinucleotide, pyridomycin, quinolinic acid, transferase
• Biological source: Streptomyces pyridomyceticus
• Total number of polymer chains: 2
• Total formula weight: 66052.74

Authors

Zhou, Z.,Yang, X.,Huang, T.,Wang, X.,Liang, R.,Zheng, J.,Dai, S.,Lin, S.,Deng, Z. (deposition date: 2022-04-05, release date: 2023-03-22, Last modification date: 2023-11-29)

Primary citation

Zhou, Z.,Yang, X.,Huang, T.,Zheng, J.,Deng, Z.,Dai, S.,Lin, S.
Bifunctional NadC Homologue PyrZ Catalyzes Nicotinic Acid Formation in Pyridomycin Biosynthesis.
Acs Chem.Biol., 18:141-150, 2023

PubMed Abstract: Pyridomycin is a potent antimycobacterial natural product by specifically inhibiting InhA, a clinically validated antituberculosis drug discovery target. Pyridyl moieties of pyridomycin play an essential role in inhibiting InhA by occupying the reduced form of the nicotinamide adenine dinucleotide (NADH) cofactor binding site. Herein, we biochemically characterize PyrZ that is a multifunctional NadC homologue and catalyzes the successive formation, dephosphorylation, and ribose hydrolysis of nicotinic acid mononucleotide (NAMN) to generate nicotinic acid (NA), a biosynthetic precursor for the pyridyl moiety of pyridomycin. Crystal structures of PyrZ in complex with substrate quinolinic acid (QA) and the final product NA revealed a specific salt bridge formed between K184 and the C3-carboxyl group of QA. This interaction positions QA for accepting the phosphoribosyl group to generate NAMN, retains NAMN within the active site, and mediates its translocation to nucleophile D296 for dephosphorylation. Combining kinetic and thermodynamic analysis with site-directed mutagenesis, the catalytic mechanism of PyrZ dephosphorylation was proposed. Our study discovered an alternative and concise NA biosynthetic pathway involving a unique multifunctional enzyme.

PubMed: 36517246
DOI: 10.1021/acschembio.2c00773

Experimental method

X-RAY DIFFRACTION (2.11 Å)