5YJF

Co-crystal structure of Human Nicotinamide N-methyltransferase (NNMT) with small molecule analog of Nicotinamide

5YJF の概要

• エントリーDOI: 10.2210/pdb5yjf/pdb
• 分子名称: Nicotinamide N-methyltransferase, S-ADENOSYL-L-HOMOCYSTEINE, 6-methoxy-1-methyl-2H-pyridine-3-carboxamide, ... (4 entities in total)
• 機能のキーワード: nnmt, na, mna, t2d, transferase
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm: P40261
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 128627.15

構造登録者

Swaminathan, S.,Birudukota, S.,Thakur, M.K.,Parveen, R.,Kandan, S.,Hallur, M.S.,Rajagopal, S.,Ruf, S.,Dhakshinamoorthy, S.,Kannt, A.,Gosu, R. (登録日: 2017-10-10, 公開日: 2018-03-21, 最終更新日: 2023-11-22)

主引用文献

Kannt, A.,Rajagopal, S.,Kadnur, S.V.,Suresh, J.,Bhamidipati, R.K.,Swaminathan, S.,Hallur, M.S.,Kristam, R.,Elvert, R.,Czech, J.,Pfenninger, A.,Rudolph, C.,Schreuder, H.,Chandrasekar, D.V.,Mane, V.S.,Birudukota, S.,Shaik, S.,Zope, B.R.,Burri, R.R.,Anand, N.N.,Thakur, M.K.,Singh, M.,Parveen, R.,Kandan, S.,Mullangi, R.,Yura, T.,Gosu, R.,Ruf, S.,Dhakshinamoorthy, S.
A small molecule inhibitor of Nicotinamide N-methyltransferase for the treatment of metabolic disorders.
Sci Rep, 8:3660-3660, 2018

PubMed Abstract: Nicotinamide N-methyltransferase (NNMT) is a cytosolic enzyme that catalyzes the transfer of a methyl group from the co-factor S-adenosyl-L-methionine (SAM) onto the substrate, nicotinamide (NA) to form 1-methyl-nicotinamide (MNA). Higher NNMT expression and MNA concentrations have been associated with obesity and type-2 diabetes. Here we report a small molecule analog of NA, JBSNF-000088, that inhibits NNMT activity, reduces MNA levels and drives insulin sensitization, glucose modulation and body weight reduction in animal models of metabolic disease. In mice with high fat diet (HFD)-induced obesity, JBSNF-000088 treatment caused a reduction in body weight, improved insulin sensitivity and normalized glucose tolerance to the level of lean control mice. These effects were not seen in NNMT knockout mice on HFD, confirming specificity of JBSNF-000088. The compound also improved glucose handling in ob/ob and db/db mice albeit to a lesser extent and in the absence of weight loss. Co-crystal structure analysis revealed the presence of the N-methylated product of JBSNF-000088 bound to the NNMT protein. The N-methylated product was also detected in the plasma of mice treated with JBSNF-000088. Hence, JBSNF-000088 may act as a slow-turnover substrate analog, driving the observed metabolic benefits.

PubMed: 29483571
DOI: 10.1038/s41598-018-22081-7

実験手法

X-RAY DIFFRACTION (2.49 Å)