Fatty acid elongation in the cytosol (FAS I system)

The de novo biosynthesis of fatty acids takes place through the cytosolic FAS I system in mammals and fungi. In FAS I system, a single multifunctional enzyme carries out the functions of beta-ketoacyl-ACP synthase, 3-oxoacyl-ACP reductase, 3-hydroxyacyl-ACP dehydratase, Enoyl-ACP reductase and ACP-acyl transferase. This systems is also present in apicomplexans such as Toxoplasma, Neospora and Cryptosporidium species and it is evident from the possessions of genes for larger multifunctional fatty acid synthase I and polyketide synthases in the gene models. The phylogenetic analysis has showed that Cryptosporidium parvum fatty acid synthase is evolutionarily related to the C. parvum polyketide synthase and also phylogenetically closer to bacterial polyketide synthases than to eukaryotic fatty acid synthase s[1]. This suggests that FAS I can be a possible drug target. In contrast to seven enzymatic domains of mamalian enzyme, C. parvum enzyme contains 21 domains  arranged in starter unit containing fatty acid ligase and an acyl-carrier protein,  three elongation modules each containing five enzymatic domains performing above mentioned functions and an acyl carrier protein domain and the termination domain [2]. Although there were no experimental studies made with T. gondii and N. caninum FASI, the cloning, expression and substrate inhibition studies of recombinant loading unit of C. parvum FASI by Zhu et al has showed that the potential substrates are fatty acids of C₁₂-C₂₄ chain length with higher preference for C₁₆ suggesting the role for Apicomplexan FAS I in elongation rather than de novo biosynthesis [3]. On the basis of the presence of three functional elongation modules and the preference for C₁₆ as substrate, it has been suggested that this enzyme catalyses three cycles of elongation adding 6 carbon chain length and produces C₂₂ fatty acids [4]. Although it is not feasible to identify the products of even larger polyketide synthase of C. parvum, it has been identified that these also prefer long-chain fatty acids with increased affinity for C₁₆ palmitoic acid [5].

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Sources and fates of metabolites