Identification of the active site of human mitochondrial malonyl‐coenzyme a decarboxylase: A combined computational study

Abstract

Malonyl-CoA decarboxylase (MCD) can control the level of malonyl-CoA in cell through the decarboxylation of malonyl-CoA to acetyl-CoA, and plays an essential role in regulating fatty acid metabolism, thus it is a potential target for drug discovery. However, the interactions of MCD with CoA derivatives are not well understood owing to unavailable crystal structure with a complete occupancy in the active site. To identify the active site of MCD, molecular docking and molecular dynamics simulations were performed to explore the interactions of human mitochondrial MCD (HmMCD) and CoA derivatives. The findings reveal that the active site of HmMCD indeed resides in the prominent groove which resembles that of CurA. However, the binding modes are slightly different from the one observed in CurA due to the occupancy of the side chain of Lys183 from the N-terminal helical domain instead of the adenine ring of CoA. The residues 300 - 305 play an essential role in maintaining the stability of complex mainly through hydrogen bond interactions with the pyrophosphate moiety of acetyl-CoA. Principle component analysis elucidates the conformational distribution and dominant concerted motions of HmMCD. MM_PBSA calculations present the crucial residues and the major driving force responsible for the binding of acetyl-CoA. These results provide useful information for understanding the interactions of HmMCD with CoA derivatives. Proteins 2016; 84:792-802. © 2016 Wiley Periodicals, Inc.

Recent Developments and Applications of the MMPBSA Method

“…In a search for compounds for the treatment of chronic kidney disease, Vitamin D receptor and cytochrome P450 were analyzed (Nagamani et al, 2016 ). Malonyl-CoA decarboxylase (Ling et al, 2016 ), sirtuins (Karaman and Sippl, 2015 ), adipocyte fatty-acid binding protein (Chen et al, 2014b ), 11β-hydroxysteroid dehydrogenase type 1 (Qian H. Y. et al, 2016 ), and protein tyrosine phosphatase 1B (Kocakaya, 2014 ) were reported for treatments of other metabolic diseases. For other diseases and disorders, targets such as pyrroline-5-carboxylate reductase for cutis laxa (Sang et al, 2017 ), renin complexes for hypertension (Tzoupis et al, 2015 ), and the type 1 receptor of TGF beta for wound healing (Gesteira et al, 2017 ) were examined.…”

Assessment of relationships between mitochondrial proteins and ischemic stroke: a bidirectional Mendelian randomization study

“…Numerous studies have suggested that MLYCD may potentially be an effective treatment for cardiovascular diseases [25,26]. MLYCD regulates intracellular malonyl-CoA levels by converting malonyl-CoA into acetyl-CoA through decarboxylation, thereby exerting a major role in the regulation of fatty acid metabolism [27]. This mechanism may be highly relevant in the regulation of mitochondrial function.…”