oxidation of glucose and other fuels. When energy demands are low, citrate is transported to the cytoplasm where it is cleaved to acetyl-CoA and OAA. Acetyl-CoA is carboxylated to form malonyl-CoA by acetyl-CoA carboxylase. The irreversible reaction takes place in two phases and is the rate-limiting step in fatty acids synthesis. Mammals have two enzymes. The soluble Acaca is expressed in the cytoplasm of lipogenic tissues. Acacb is expressed in heart and muscle and to some extent in the liver; in these tissues malonyl-CoA acts as an inhibitor of CPT-1 to control the entry of fatty acids into the mitochondrion for beta-oxidation. Malonyl-CoA is also used in the elongation of fatty acids. The biotin-dependent Acac enzymes consist of three domains - BCCP, BC and CT that reside on the same polypeptide chain in eukaryotes. The active form is a polymer resulting from the aggregation of dimers, a reaction promoted by dephosphorylation and inhibited by phosphorylation; the inhibitory role of kinases is better documented. AMPK exerts a dual role: it inhibits fatty acid synthesis and activates their degradation. In addition, citrate provides feed-forward activation while fatty acids act as negative feedback inhibitors. The next reactions, 7 types for a total of 37 steps, take place on fatty acid synthase, probably one of the most complex multifunctional eukaryotic enzymes. The active synthase is a head-to-tail dimer. From the N- to the C-terminus of the monomer, the abbreviated activities are KS, AT/MT, DH, ER, KR, ACP and TE and they can be grouped into three domains. The reactions start with AT/MT transferring an acetyl group from acetyl-CoA to the thiol group of cysteine at the active site of KS and a malonyl group from malonyl-CoA to the thiol group of the pantethein prosthetic group of ACP; they are condensed to acetoacetyl-ACP by KS. Sequential reduction by KR, dehydration by DH and another reduction by ER yield the saturated acyl-ACP which is then transferred back to the cysteine thiol of KS for another cycle of reactions. Overall the pathway is a series of cycles where each cycle ends in an acyl-ACP two carbons longer than the previous one. After 7 cycles, palmitoyl-ACP is cleaved from the enzyme by TE to yield palmitate. Depending on cellular demands the newly synthesized fatty acids can be esterified to triacylglycerol, or converted to longer chain saturated and unsaturated fatty acid by elongases and desaturases to provide important membrane components or fatty acid derivatives. The pathway is regulated at many levels, including transcriptional - the role of the SREBP signaling pathway in the expression of Acly, Acaca and Fasn itself, is well documented. Overexpression of ACLY, ACACA and FASN has been observed in several human cancers. To see the ontology report for GViewer, annotations and download, click here
[Click to see the ontology report for associated GO term - GO:0006633, KEGG map map00061]...(less)