Inhibitors of Fatty Acid Synthesis and Elongation
FATTY ACID BIOSYNTHESIS AND ELONGATION
Crucial first step: The first enzyme of fatty acid synthesis is acetyl CoA-carboxylase (ACCase; EC 184.108.40.206), which catalyzes the ATP-dependent carboxylation of acetyl-CoA to form malonyl-CoA . ACCase carries out the first committed step and is thus the regulatory site for the whole pathway. The enzyme is composed of two monomers with different functions: a biotin carboxylase complex and a carboxyltransferase complex. Higher plants have two forms of ACCase: a eukaryotic, cytosolic form that is mostly resistant to herbicides and a prokaryotic, plastidic form that is susceptible to herbicides. The plastidic enzyme is further subdivided into two isoforms: a dimeric form found in most monocots and all dicots, and an unusual multidomain form found only in graminaceous monocots. Biochemical investigations on the mechanism of action for ACCase-inhibiting herbicides show that they interact with a 400-amino acid region of the carboxyltransferase domain of the enzyme.
In plants, fatty acids are synthesized in plastids. According to the Endosymbiont Theory, plastids are the modern, evolutionary descendents of free-living prokaryotes that were engulfed and retained by larger bacteria. These endosymbionts gradually evolved into chloroplasts and mitochondria. The fatty acid biosynthetic pathway in plant plastids is very similar to the pathway in modern prokaryotes, providing support for this theory. The pathway begins with the addition of two-carbon units to acetyl-CoA (from glycolysis) to create 16- or 18-carbon fatty acids. These molecules are either exported into the cytosol where they are integrated into membranes or other cellular components, or are further elongated into waxes, suberin, or cutin.
Remainder of the pathway: Malonyl-CoA is elongated into fatty acids by the stepwise addition of two-carbon acetyl units by the enzyme fatty acid synthase. Synthesis by this process continues to produce 16:0-acyl carrier protein (ACP) or 18:0-ACP saturated fatty acids. Terminal reactions of fatty acid synthesis include thioester bond hydrolysis, acyl desaturation, and transfer of the acyl group to a glycerolipid. Of these reactions, glycerolipid synthesis deserves special mention since these are the main structural lipids of all cellular membranes except those of the chloroplast. Briefly, 16:0 and 18:1 fatty acids are exported from the chloroplast to the endoplasmic reticulum (ER) as their acyl-CoA moieties, where they are incorporated into phosphatidylcholine and other phospholipids. The diversity of fatty acids is immense, with over 200 different fatty acids identified in higher plants.
Fatty Acid Elongation: In plants, very long-chain fatty acids (VLCFAs) are particularly important as membrane components and as cuticular and epicuticular waxes. Fatty acids from the chloroplast are exported into the endoplasmic reticulum, where a family of elongase enzymes first convert free long-chain fatty acids into fatty acyl-CoA esters. The same enzymes subsequently elongate these molecules up to 34 carbons to create waxes and suberin.
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