Pentose phosphate pathway, fatty acid oxidationc.

Fatty acid biosynthesis occurs through the condensation of C2 units and is coupled to the hydrolysis of ATP (2). The process of fatty acid synthesis involves two regulatory steps. The first step is the carboxylation of acetyl-CoA in the cytosol to form malonyl CoA (Figure 1). Catalyzed by the biotin-dependent acetyl-CoA carboxylase, an enzyme that transfers CO2 to substrates, this step is the rate-limiting step and therefore a very important site in the regulation of fat accumulation. If sufficient biotin is not available for carboxylation of acetyl-CoA, fatty acid synthesis will not occur. The second major point of regulation in fatty acid synthesis is the decarboxylation of the malonyl group, catalyzed by fatty acid synthase. The multienzymatic activity of fatty acid synthase regulates fatty acid synthesis (Figure 2).

NADPH2 supplies the necessary reducing equivalents for the Fatty Acid Synthesis Pathway.

Synthesis of succinyl coenzyme A
-Gastroectomy= B12 deficiency= Propionate and methylmalonate are excreted in the urine
-Mutase reaction is one of only 2 reactions in the body that require vitamin B12

Oxidation of unsaturated fatty acids
-Provides less energy than saturated fatty acids because unsaturated FA are less highly reduced and therefore fewer reducing equivalents can be produced
-Oxidation of monounsaturated FA's such as oleic acid 18:1 (9) requires 1 additional enzyme, 3,2-enoyl CoA isomerase which converts 3-cis derivative to 2 trans derivative needed as a substrate by enoyl CoA hydratase
-Oxidation of polyunsaturated fatty acids such as linoleic acid 18:2 (9,12) needs an NADPH-dependent 2,4-dienoyl CoA reductase in addition to isomerase

B-oxidation in peroxisome
-Very long FA's (22 carbons+) undergo preliminary B-oxidation in peroxisomes because they are the primary site of synthetase that activates fatty acids of this length
-Shortened fatty acid (linked to carnitine) diffuses to a mitochondria for further oxidation
-Dehydrogenation in peroxisomes is catalyzed by a FAD-containing acyl CoA oxidase
-FADH2 produced is oxidized by molecular oxygen which is reduced to H2O2 by catalase
-Zellweger syndrome= Defect in ability to target matrix proteins to peroxisomes
-X-linked adrenoleukodystrophy= Defect in transport of VLCFAs across peroxisomal membrane leading to accumulation in blood and tissues

Peroxisomal alpha-oxidation of fatty acids
-Branched chain phytanic acid
-Product of chlorophyll metabolism is not a substrate for acyl CoA dehydrogenase because of methyl group on its B-carbon
-It is hydroxylated at alpha carbon by phytanoyl CoA alpha-hydroxylase (PhyH), carbon 1 is released as CO2, and the product, 19- carbon pristanal is oxidized to pristanic acid which is activated to its CoA derivative and undergoes B-oxidation
-Refsum disease: A rare, autosomal recessive disorder caused by a deficiency of peroxisomal PhyH resultrs in accumulation of phytanic acid in plasma and tissues.

What is the rate limiting step of fatty acid synthesis.

NADPHAnswer is c.Two major enzyme complexes are involved in the synthesis of fatty acids.

The tissue content of highly unsaturated fatty acids (HUFA) such as arachidonic acid and docosahexaenoic acid is maintained in a narrow range by feedback regulation of synthesis. Delta-6 desaturase (D6D) catalyzes the first and rate-limiting step of the HUFA synthesis. Recent identification of a human case of D6D deficiency underscores the importance of this pathway. Sterol regulatory element binding protein-1c (SREBP-1c) is a key transcription factor that activates transcription of genes involved with fatty acid synthesis. We recently identified sterol regulatory element (SRE) that is required for activation of the human D6D gene by SREBP-1c. Moreover, the same SRE also mediates the suppression of the D6D gene by HUFA. The identification of SREBP-1c as a key regulator of D6D suggests that the major physiological function of SREBP-1c in liver may be the regulation of phospholipid synthesis rather than triglyceride synthesis. Peroxisome proliferators (PP) induce fatty acid oxidation enzymes and desaturases in rodent liver. However, the induction of desaturases by PP is slower than the induction of oxidation enzymes. This delayed induction may be a compensatory reaction to the increased demand of HUFA caused by increased HUFA oxidation and peroxisome proliferation in PP administration. Recent studies have demonstrated a critical role of peroxisomal β-oxidation in DHA synthesis, and identified acyl CoA oxidase and D-bifunctional protein as the key enzymes.