O-Acyltransferases

High-fat diet studies with DGATl-/- and DGATl+/- mice demonstrated that the absence of DGAT1 activity may lead to increased insulin sensitivity, leptin sensitivity, protection against diet-induced obesity, and protection against liver steatosis [40-43]. 

DGAT2- - mice suffer from severe hypolipidemia and do not survive postnatally [44]. However, this may be only a developmental phenomenon, since adult obese mice treated with DGAT2 antisense oligonucleotides were viable and showed improved hepatic steatosis along with improved insulin sensitivity [45]. 

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This enzyme [EC 2.3.1.42], also known as glycerone-phosphate O-acyltransferase, catalyzes the reaction of an acyl-CoA with dihydroxyacetone phosphate (or, glyc-erone phosphate) to produce coenzyme A and an acyldi-hydroxyacetone phosphate (or, an acylglycerone phosphate). The acyl-CoA derivatives of pahnitate, stearate, and oleate can all be utilized as substrates, with highest activity observed with palmitoyl-CoA. 

ALKYLGLYCEROL KINASE 1-ALKYLGLYCEROPHOSPHOCHOLINE O-ACYLTRANSFERASE Alkylglycerophosphoethanolamine phosphodiesterase,... 

Figure 7.22 N-, O-Acyltransferase reactions of arylhydroxamic acid. Ar = aryl group.

Figure 1 Structural and bioconverting relationships among tylosin, AIV, and its related acyltylosins. (A) Chemical structures of tylosin, AIV, and its related acyltylosins. (B) Biotransformation of tylosin to AIV by two types of macrolide acyltransferases in S. ther-motolerans 3-O-acyltransferase and 4"-0-acyltransferase catalyze acetylation at the 3-hydroxyl group of tylonolide and isovalerylation at the 4"-hydroxyl group of mycarose, respectively.

Figure 4 Comparison of amino acid sequences of three O-acyltransferases for macrolide antibiotics. Amino acid sequences encoded by acyA [20], mdmB (midecamycin 3-0-acetyltransferase) [21], and acyBl (carE) [15,18] are aligned according to the multialignment application program of GENETYX-MAC (Software Development Co., Tokyo, Japan). The residue number is indicated at the right end of each sequence. Identities across all three sequences are denoted by asterisks. (From Ref. 20.)...

Figure 11 The putative catabolic pathway of L-leucine and its implications for strain improvement. For a promising host strain, the pathway to be blocked is indicated with thick double lines and the pathways to be fortified are indicated with thick arrows. Abbreviations for enzymes participating in the L-leucine catabolism and the acylation of tylosin VDH, valine (branched-chain amino acid) dehydrogenase BCDFI, branched-chain a-keto acid dehydrogenase IVD (AcdH), isovaleryl-CoA dehydrogenase (acyl-CoA dehydrogenase) MCC, 3-methylcrotonyl-CoA carboxylase EH, enoyl-CoA hydratase AcyA, mac-rolide 3-O-acyltransferase AcyBl, macrolide 4"-(9-acyltransferase.

A Arisawa, H Tsunekawa, K Okamura, R Okamoto. Nucleotide sequence analysis of the carbomycin biosynthetic genes including the 3-O-acyltransferase gene from Streptomyces thermotolerans. Biosci Biotechnol Biochem 59 582-588, 1995. 

O Hara, CR Hutchinson. A macrolide 3-O-acyltransferase gene from the mideca-mycin-producing species Streptomyces mycarofaciens. JBacteriol 174 5141-5144, 1992. 

A Tanaka, T Terasawa, H Hagihara, Y Sakuma, N Ishibe, M Sawada, H Takasugi, H Tanaka. Inhibitors of acyl-CoAxholesterol O-acyltransferase. 2. Identification and structure-activity relationships of a novel series of N-alkyl-N-(heteroaryl-sub-stituted benzyl)-N -arylureas. JMed Chem 41 2390-2410, 1998. 

Diczfalusy MA, Bjorkhem I, Einarsson C. Alexson SEH. Formation of fatty acid ethyl esters in rat Uver microsomes. Evidence for a key role for acyl-CoA ethanol O-acyltransferase. Eur J Biochem 1999 259 404-411. 

A short-term regulation mechanism for cholesterol 7a-hydroxylase activity has been investigated recently in rat liver. The enzyme appears to exist in two forms, which are interconverted by cytosolic fiictors (K12). These foctors may correspond to a protein kinase and a phosphatase, which have been proposed to regulate cholesterol 7a-hydroxylase activity by a phosphorylation (active form)-dephosphorylation (inactive form) mechanism (S9). Another enzyme utilizing cholesterol as substrate, acyl-CoA cholesterol O-acyltransferase (EC 2.3.1.26), may also be regulated in this way, while the biosynthetic enzyme, HMC-CoA reductase, is inhibited in the phosphory-lated form (SIO). Thus, short-term regulation of the concentration of un-esterified cholesterol in the liver may be achieved by coordinate control of these three key enzymes in cholesterol metabolism by reversible phosphorylation (SIO). 

Purpactinc. Metabolites of PeniciUium purpuroge-num, potent inhibitors of acyl-CoA cholesterol O-acyltransferase (ACAT). The related penicillide from P. purpurogenum and P. vermiculatum lacks the acetyl group at 0-r. 

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