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Elucidation of the Mechanism of Ribose Conjugation in a Pyrazole-Containing Compound in Rodent Liver

Elucidation of the Mechanism of Ribose Conjugation in a Pyrazole-Containing Compound in Rodent Liver

Hoa Le, Kevin A Ford, S Cyrus Khojasteh, Peter W Fan

Xenobiotica. 2013 Mar;43(3):236-45.

PMID: 22931212

Abstract:

1. Here we report on the mechanism of ribose conjugation, through NADH as a cofactor, of a pyrazole-containing compound (PT). Incubation of PT in rat liver microsomes supplemented with NADP⁺/H, NAD⁺/H, and β-nicotinamide mononucleotide (NMN) resulted in complete conjugation to the adenine dinucleotide phosphate conjugate (ADP-C), adenine dinucleotide conjugate (AD-C), and 5-phosphoribose conjugate (Rib-C1), respectively. In hepatocytes, PT predominantly formed three ribose conjugates: Rib-C1, the ribose conjugate (Rib-C2), and the carboxylic acid of Rib-C2 (Rib-C3). 2. Phosphatase inhibitors were added to hepatocyte incubations. AD-C was detected in this reaction, which suggests that one of the major pathways for the formation of the ribose conjugates is through NAD⁺/H. When AD-C was incubated with phosphatase, Rib-C1 and Rib-C2 formed. 3. To understand the in vivo relevance of this metabolic pathway, rats were dosed with PT and Rib-C2 was found in the urine. 4. Structure-activity relationship shows that replacement of the distal thiazole group in the PT to a phenyl group abolishes this conjugation. Three amino acid residues in the active site preferentially interact with the sulfur atom in the thiazole of PT. 5. In summary, PT forms direct AD-C in hepatocytes, which is further hydrolyzed by phosphatase to give ribose conjugates.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1094617	β-Nicotinamide mononucleotide		1094-61-7	Price

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