0 mutations fatty acid synthesis

The mutant enzyme would be persistently active because it could not be inhibited by phosphorylation. Fatty acid synthesis would be abnormally active. Such a mutation might lead to obesity. 

The final step in each round of fatty acyl elongation in E. coli is the NADH-dependent reduction of the trans double bond, catalyzed by the homotetrameric (subunit mass of 29 kDa) NADH-dependent enoyl-ACP reductase I (encoded by fabl). The Fabl amino acid sequence is similar (34% identical) to the product of a gene (called inhA) from mycobacteria. InhA is involved in mycolic acid biosynthesis (A. Banerjee, 1994). The synthesis of these unusual 70-80 carbon mycobacterial acids requires a pathway composed of enzymes essentially identical to those of fatty acid synthesis. Missense mutations within the inhA gene result in resistance to the anti-tuberculosis drugs, isoniazid and ethionamide. The crystal structures of Fabl and InhA have been solved, and are virtually superimposable for most... 

The presence or absence of the ability to synthesize certain fatty acids may then serve as a basis for establishing relationships between species. The value of the study of the comparative biochemistry of fatty acid synthesis depends on the point on the evolutionary time scale when the ability to synthesize a particular fatty acid appeared. There is no reason why the same gene mutation should not occur in different groups at different times. But while a comparatively recent mutation may be of little interest to the comparative biochemist, certain mutations which occurred in the early evolution of primitive organisms may be useful in enabling phylogenetic pathways to be traced. 

LCAT catalyzes the transfer of a preferentially unesterified fatty acid from the sn-2 position of phosphatidylcholine to the 3/i-hydroxy group of cholesterol, and thereby produces lysophosphatidylcholine and a cholesteryl ester [50]. Depending on the mutation in the LCAT gene, homozygous or compound heterozygous patients present with one of two clinical phenotypes, classical LCAT deficiency or fish-eye disease [58, 85]. Classical LCAT deficiency is caused by a broad spectrum of missense and non-sense mutations that interfere with the synthesis or secretion or affect the catalytic activity of LCAT [10]. Fish-eye disease is caused by a limited number of missense point mutations that alter the surface polarity, and thereby interfere with the binding of the enzyme to apoA-I containing lipoproteins [77]). 

Polled hereford calves in Australia develop maple syrup urine disease relatively often/ 6 One cause was established as a mutation that introduces a stop codon that causes premature termination within the leader peptide during synthesis of the thiamin diphosphate-dependent El subunit. A similar biochemical defect in a mutant of Bacillus subtilis causes difficulties for this bacterium, which requires branched-chain fatty acids in its membranes. Branched acyl-CoA derivatives are needed as starter pieces for their synthesis (Chapter 29). With the oxidative decarboxylation of the necessary oxoacids blocked, the mutant is unable to grow unless supplemented with branched-chain fatty acids. 

Mutations in desatl affect HC, resulting in a very large decrease in 7-HC in males, and in 7- and 7,11-HC in females, with a parallel increase in saturated HC synthesis (Labeur el al., 2002 Ueyama el al., 2005 Marcillac et al., 2005a,b). Lipid metabolism is impaired too, with both quantitatively and qualitatively altered fatty acid biosynthesis the overall quantity of fatty acids was shown to be reduced by half and that of vaccenic acid, the common precursor to 7-HC in both sexes, reduced by a factor of six in a desatl mutant (Ueyama et al., 2005). 

Current evidence suggests that accumulation of fat in NAFLD is a consequence of insulin resistance. A variety of mechanisms may lead to insulin resistance, including genetic predisposition, increased concentrations of free fatty acids, and presence of cytokines such as tumor necrosis factor alpha (TNF-a). Since TNF-a is produced by fat cells, correlates with body fat, and is critical to development of insulin resistance in obesity,it may be a key factor in development of NAFLD. The pathogenesis is likely to be more complicated, however, as a variety of other factors lead to increased fat accumulation in the liver, including increased carbohydrate intake, certain drugs, and mutations in lipid synthesis, but have not been associated with development of NASH. 

---