Swaminathan Srinivasan, Birudukota Swarnakumari, Thakur Manish Kumar, Parveen Reejuana, Kandan Saravanan, Juluri Suresh, Shaik Shama, Anand Niranjan Naranapura, Burri Raghunadha Reddy, Kristam Rajendra, Hallur Mahanandeesha Siddappa, Rajagopal Sridharan, Schreuder Herman, Langer Thomas, Rudolph Christine, Ruf Sven, Dhakshinamoorthy Saravanakumar, Gosu Ramachandraiah, Kannt Aimo
Department of Structural Biology, Jubilant Biosys Ltd, Bangalore 560022, India.
Department of Biology, Jubilant Biosys Ltd, Bangalore 560022, India.
Biochem Biophys Res Commun. 2017 Sep 16;491(2):416-422. doi: 10.1016/j.bbrc.2017.07.087. Epub 2017 Jul 15.
Nicotinamide N-methyltransferase (NNMT) is a S-adenosyl-l-methionine (SAM)-dependent enzyme that catalyzes N-methylation of nicotinamide (NA) and other pyridines to form N-methyl pyridinium ions. Here we report the first ternary complex X-ray crystal structures of monkey NNMT and mouse NNMT in bound form with the primary endogenous product, 1-methyl nicotinamide (MNA) and demethylated cofactor, S-adenosyl-homocysteine (SAH) determined at 2.30 Å and 1.88 Å respectively. The structural fold of these enzymes is identical to human NNMT. It is known that the primary endogenous product catalyzed by NNMT, MNA is a specific inhibitor of NNMT. Our data clearly indicates that the MNA binds to the active site and it would be trapped in the active site due to the formation of the bridge between the pole (long helix, α3) and long C-terminal loop. This might explain the mechanism of MNA acting as a feedback inhibitor of NNMT.
烟酰胺N-甲基转移酶（NNMT）是一种依赖S-腺苷-L-甲硫氨酸（SAM）的酶，它催化烟酰胺（NA）和其他吡啶的N-甲基化反应，形成N-甲基吡啶鎓离子。在此，我们报道了猴源NNMT和鼠源NNMT与主要内源性产物1-甲基烟酰胺（MNA）以及去甲基化辅因子S-腺苷高半胱氨酸（SAH）结合形式的首个三元复合物X射线晶体结构，分辨率分别为2.30 Å和1.88 Å。这些酶的结构折叠与人源NNMT相同。已知NNMT催化的主要内源性产物MNA是NNMT的特异性抑制剂。我们的数据清楚地表明，MNA结合到活性位点，并且由于在极（长螺旋，α3）和长C末端环之间形成桥，它会被困在活性位点。这可能解释了MNA作为NNMT反馈抑制剂的作用机制。
