Fatty acids are synthesized de novo from acetyl-CoA and malonyl-CoA through a series of reactions mediated by acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS). In rodents, the principal fatty acid produced by FAS is palmitic acid (16:0). Sterol regulatory elementbinding proteins (SREBPs) enhance the transcription of many genes responsible for fatty acid synthesis. In transgenic mice that overexpress SREBPs in liver, the rate of fatty acid synthesis is markedly increased, owing to the activation of these biosynthetic genes, which include ATP citrate lyase, ACC, FAS, and stearoyl-CoA desaturase. The fatty acids that accumulate in livers of SREBP transgenic mice are 18 carbons rather than 16 carbons in length, suggesting that the enzymes required for the elongation of palmitic to stearic acid may be induced. Here, we report the cDNA cloning of a murine long chain fatty acyl elongase (LCE) that was identified initially by oligonucleotide array analysis of mRNA from SREBP transgenic mouse livers. LCE mRNA is highly expressed in liver and adipose tissue. The cDNA encodes a protein of 267 amino acids that shares sequence identity with previously identified very long chain fatty acid elongases. Cells that overexpress LCE show enhanced addition of 2-carbon units to C12-C16 fatty acids. We provide evidence that LCE catalyzes the rate-limiting condensing step in this reaction. The current studies suggest that mouse LCE expression is increased by SREBPs and that the enzyme is a component of the elusive mammalian elongation system that converts palmitic to stearic acid.In mammals, most of the fatty acids that are synthesized de novo possess chain lengths of 16 -18 carbons. These long chain fatty acids constitute more than 90% of all fatty acids present in cells. They are important components of membranes, and they represent the largest energy storage reservoir in animals.The highest rate of de novo fatty acid synthesis occurs in liver, which converts excess glucose into fatty acids for storage and transport. Glycolysis converts glucose to pyruvate, which is converted to citrate in the mitochondria and transported to the cytosol. Cytosolic ATP citrate lyase generates acetyl-CoA, the precursor of fatty acids and cholesterol. Acetyl-CoA is carboxylated by acetyl-CoA carboxylase (ACC) 1 to form malonyl-CoA. The multifunction enzyme FAS uses malonyl-CoA, acetyl-CoA, and NADPH to elongate fatty acids in 2-carbon increments (1). The principal end product of FAS in rodents is palmitic acid, which contains 16 carbons and is designated 16:0 (2). A high proportion of this palmitic acid is then converted to stearate (18:0).The mammalian enzymes that elongate palmitic acid to stearic acid have not been identified; however, the elongation activity has been localized to the endoplasmic reticulum (3). The fatty acid elongase uses malonyl-CoA as the 2-carbon donor. Each 2-carbon addition requires four sequential reactions: 1) condensation between a fatty acyl-CoA and malonyl-CoA to form a 3-ketoacyl-CoA, 2) reduction of the 3-ketoa...

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Addition of Zn(n-Bu(3)Sn)(2) to prochiral aldehydes affords anti-alpha,beta-dialkoxy- and anti-alpha-alkoxy-beta-aminostannanes in good yield (up to 77%) and excellent diastereoselectivity (up to 98% de). syn-Isomers are accessed from the initial adducts via Mitsunobu inversion/saponification. The corresponding thionocarbamates undergo mild Cu(I)-mediated cross-coupling with a variety of organic halides, inter alia, allylic, cinnamylic, propargylic, and acetylenic, with retention of configuration. [reaction: see text]

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