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 gondii 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 synthases [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]. 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].

 

Enzyme EC Number Gene id
Fatty acid synthase I (mammlaian/fungal type) 2.3.1.85 CMU_001350
Fatty acid synthase I (mammlaian/fungal type) 2.3.1.85 CMU_018010
Cytosolic acetyl-CoA carboxylase (ACCase2) 6.3.4.14; 6.4.1.2 CMU_005960
Acyl carrier protein none CMU_013770

 

Open in a new window

 

 

Sources and fates of metabolites

 

Substrate Source pathways Product Fate pathways
Fatty acid (upto C16) Host Fatty acid (upto C22) Fatty acid elongation in the ER, Phosphatidylethanolamine and phosphatidylserine metabolism
Acetyl-CoA Tricarboxylic acid (TCA) cycle, Pyruvate metabolism    
ACP CoA biosynthesis