PMID- 25873848
OWN - NLM
STAT- PubMed-not-MEDLINE
DCOM- 20150415
LR  - 20200929
IS  - 1598-866X (Print)
IS  - 2234-0742 (Electronic)
IS  - 1598-866X (Linking)
VI  - 13
IP  - 1
DP  - 2015 Mar
TI  - Comparative Modeling and Molecular Dynamics Simulation of Substrate Binding in 
      Human Fatty Acid Synthase: Enoyl Reductase and beta-Ketoacyl Reductase Catalytic 
      Domains.
PG  - 15-24
LID - 10.5808/GI.2015.13.1.15 [doi]
AB  - Fatty acid synthase (FASN, EC 2.3.1.85), is a multi-enzyme dimer complex that 
      plays a critical role in lipogenesis. This lipogenic enzyme has gained importance 
      beyond its physiological role due to its implications in several clinical 
      conditions-cancers, obesity, and diabetes. This has made FASN an attractive 
      pharmacological target. Here, we have attempted to predict the theoretical models 
      for the human enoyl reductase (ER) and beta-ketoacyl reductase (KR) domains based on 
      the porcine FASN crystal structure, which was the structurally closest template 
      available at the time of this study. Comparative modeling methods were used for 
      studying the structure-function relationships. Different validation studies 
      revealed the predicted structures to be highly plausible. The respective 
      substrates of ER and KR domains-namely, trans-butenoyl and beta-ketobutyryl-were 
      computationally docked into active sites using Glide in order to understand the 
      probable binding mode. The molecular dynamics simulations of the apo and holo 
      states of ER and KR showed stable backbone root mean square deviation 
      trajectories with minimal deviation. Ramachandran plot analysis showed 96.0% of 
      residues in the most favorable region for ER and 90.3% for the KR domain, 
      respectively. Thus, the predicted models yielded significant insights into the 
      substrate binding modes of the ER and KR catalytic domains and will aid in 
      identifying novel chemical inhibitors of human FASN that target these domains.
FAU - John, Arun
AU  - John A
AD  - Centre for Bioinformatics, Vision Research Foundation, Sankara Nethralaya, 
      Nungambakkam, Chennai 600-006, India.
FAU - Umashankar, Vetrivel
AU  - Umashankar V
AD  - Centre for Bioinformatics, Vision Research Foundation, Sankara Nethralaya, 
      Nungambakkam, Chennai 600-006, India.
FAU - Krishnakumar, Subramanian
AU  - Krishnakumar S
AD  - Larsen and Toubro Department of Ocular Pathology, Vision Research Foundation, 
      Sankara Nethralaya, Nungambakkam, Chennai 600-006, India.
FAU - Deepa, Perinkulam Ravi
AU  - Deepa PR
AD  - Department of Biological Sciences, Birla Institute of Technology and Science, 
      Pilani, Rajasthan 333031, India.
LA  - eng
PT  - Journal Article
DEP - 20150331
PL  - Korea (South)
TA  - Genomics Inform
JT  - Genomics & informatics
JID - 101223836
PMC - PMC4394236
OTO - NOTNLM
OT  - comparative modeling
OT  - docking
OT  - enoyl reductase
OT  - fatty acid synthase
OT  - beta-ketoacyl reductase molecular dynamics simulation
EDAT- 2015/04/16 06:00
MHDA- 2015/04/16 06:01
PMCR- 2015/03/01
CRDT- 2015/04/16 06:00
PHST- 2014/11/25 00:00 [received]
PHST- 2015/02/04 00:00 [revised]
PHST- 2015/02/04 00:00 [accepted]
PHST- 2015/04/16 06:00 [entrez]
PHST- 2015/04/16 06:00 [pubmed]
PHST- 2015/04/16 06:01 [medline]
PHST- 2015/03/01 00:00 [pmc-release]
AID - 10.5808/GI.2015.13.1.15 [doi]
PST - ppublish
SO  - Genomics Inform. 2015 Mar;13(1):15-24. doi: 10.5808/GI.2015.13.1.15. Epub 2015 
      Mar 31.