Diglyceride acyltransferase

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diacylglycerol O-acyltransferase
Identifiers
EC number 2.3.1.20
CAS number 9029-98-5
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / EGO
diacylglycerol O-acyltransferase homolog 1 (mouse)
Identifiers
Symbol DGAT1
Entrez 8694
HUGO 2843
OMIM 604900
RefSeq NM_012079
UniProt O75907
Other data
Locus Chr. 8 q24.3
diacylglycerol O-acyltransferase homolog 2 (mouse)
Identifiers
Symbol DGAT2
Entrez 84649
HUGO 16940
OMIM 606983
RefSeq NM_032564
UniProt Q96PD7
Other data
Locus Chr. 11 q13.3

Diglyceride acyltransferase (or O-acyltransferase), DGAT, catalyzes the formation of triglycerides from diacylglycerol and Acyl-CoA. The reaction catalyzed by DGAT is considered the terminal and only committed step in triglyceride synthesis and to be essential for the formation of adipose tissue.[1] The protein is homologous to other membrane-bound O-acyltransferases.

Isoforms[edit]

There are two isozymes of DGAT encoded by the genes DGAT1[2] and DGAT2.[3] Although both isozymes catalyze similar reactions, they have no sequence homology to each other.

Knockout studies[edit]

Mice with genetic disruption of the dgat1 or dgat2 genes have been made by the Farese laboratory at UCSF. Surprisingly, DGAT1−/− mice[4] are healthy and fertile and have no changes in triglyceride levels. These mice are also lean and resistant to diet-induced obesity, consequently generating interest in DGAT1 inhibitors for the treatment of obesity. In contrast, DGAT2−/− mice[5] have reduced triglyceride levels but are lipopenic, suffer from skin barrier abnormalities (including the inability to retain moisture), and die shortly after birth.

Therapeutic application[edit]

DGAT-1 inhibitors have potential for the treatment of obesity[6][7] and a number of DGAT-1 inhibitors are in clinical trials for this indication.[8]

References[edit]

  1. ^ Cases S, Smith SJ, Zheng YW, Myers HM, Lear SR, Sande E, Novak S, Collins C, Welch CB, Lusis AJ, Erickson SK, Farese RV (1998). "Identification of a gene encoding an acyl CoA:diacylglycerol acyltransferase, a key enzyme in triacylglycerol synthesis". Proc. Natl. Acad. Sci. U.S.A. 95 (22): 13018–23. doi:10.1073/pnas.95.22.13018. PMC 23692. PMID 9789033. 
  2. ^ Oelkers P, Behari A, Cromley D, Billheimer JT, Sturley SL (October 1998). "Characterization of two human genes encoding acyl coenzyme A:cholesterol acyltransferase-related enzymes". J. Biol. Chem. 273 (41): 26765–71. doi:10.1074/jbc.273.41.26765. PMID 9756920. 
  3. ^ Cases S, Stone SJ, Zhou P, Yen E, Tow B, Lardizabal KD, Voelker T, Farese RV (October 2001). "Cloning of DGAT2, a second mammalian diacylglycerol acyltransferase, and related family members". J. Biol. Chem. 276 (42): 38870–6. doi:10.1074/jbc.M106219200. PMID 11481335. 
  4. ^ Smith SJ, Cases S, Jensen DR, Chen HC, Sande E, Tow B, Sanan DA, Raber J, Eckel RH, Farese RV (May 2000). "Obesity resistance and multiple mechanisms of triglyceride synthesis in mice lacking Dgat". Nat. Genet. 25 (1): 87–90. doi:10.1038/75651. PMID 10802663. 
  5. ^ Stone SJ, Myers HM, Watkins SM, Brown BE, Feingold KR, Elias PM, Farese RV (March 2004). "Lipopenia and skin barrier abnormalities in DGAT2-deficient mice". J. Biol. Chem. 279 (12): 11767–76. doi:10.1074/jbc.M311000200. PMID 14668353. 
  6. ^ Chen HC, Farese RV (March 2005). "Inhibition of triglyceride synthesis as a treatment strategy for obesity: lessons from DGAT1-deficient mice". Arterioscler. Thromb. Vasc. Biol. 25 (3): 482–6. doi:10.1161/01.ATV.0000151874.81059.ad. PMID 15569818. 
  7. ^ Cheng D, Iqbal J, Devenny J, Chu CH, Chen L, Dong J, Seethala R, Keim WJ, Azzara AV, Lawrence RM, Pelleymounter MA, Hussain MM (October 2008). "Acylation of acylglycerols by acyl coenzyme A:diacylglycerol acyltransferase 1 (DGAT1). Functional importance of DGAT1 in the intestinal fat absorption". J. Biol. Chem. 283 (44): 29802–11. doi:10.1074/jbc.M800494200. PMC 2662058. PMID 18768481. 
  8. ^ "Pfizer, Bristol finalize deal on metabolic drugs". Reuters. 2007-08-27. Retrieved 2007-08-27.