Elongation of polyunsaturated fatty acids in trypanosomatids

Livore, Verónica Inés; Tripodi, Karina Eva Josefina; Uttaro, Antonio D.

doi:10.1111/j.1742-4658.2006.05581.x

Cited by 39 publications

(62 citation statements)

References 31 publications

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“…Although the apicomplexan elongases do not form a monophyletic clade, all of the protozoans, including both apicomplexans and the kinetoplastids (Trypanosoma and Leishmania), remain clustered together. Similar to the case for previous phylogenetic reconstructions (17), the putative kinetoplastid elongases group together in a clade exclusive to this group of parasites. With respect to putative saturated fatty acid elongases among the apicomplexans, they form two clades, both of which appear to be closely related to the ELO6 family of saturated fatty acid elongases.…”

Section: Resultssupporting

confidence: 68%

Cryptosporidium parvum Long-Chain Fatty Acid Elongase

2007

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We report the presence of a new fatty acyl coenzyme A (acyl-CoA) elongation system in Cryptosporidium and the functional characterization of the key enzyme, a single long-chain fatty acid elongase (LCE), in this parasite. This enzyme contains conserved motifs and predicted transmembrane domains characteristic to the elongase family and is placed within the ELO6 family specific for saturated substrates. CpLCE1 gene transcripts are present at all life cycle stages, but the levels are highest in free sporozoites and in stages at 36 h and 60 h postinfection that typically contain free merozoites. Immunostaining revealed localization to the outer surface of sporozoites and to the parasitophorous vacuolar membrane. Recombinant CpLCE1 displayed allosteric kinetics towards malonyl-CoA and palmitoyl-CoA and Michaelis-Menten kinetics towards NADPH. Myristoyl-CoA (C 14:0 ) and palmitoyl-CoA (C 16:0 ) display the highest activity when used as substrates, and only one round of elongation occurs. CpLCE1 is fairly resistant to cerulenin, an inhibitor for both type I and II fatty acid synthases (i.e., maximum inhibitions of 20.5% and 32.7% were observed when C 16:0 and C 14:0 were used as substrates, respectively). These observations ultimately validate the function of CpLCE1.As one of the vital compounds for all organisms, fatty acids of 14 to 18 carbons in length comprise the bulk of cellular fatty acids that serve structural and biological functions, and they are usually the major products of de novo synthesis in most cells. These long-chain fatty acids play important roles in many biological functions such as energy metabolism and membrane structure. There are several metabolic pathways that produce long-chain fatty acids, most notably the type I and type II fatty acid synthases (FASs). The type I enzymes of mammals and fungi are typically cytosolic and composed of multiple enzymes arranged into domains of one or two large polypeptides (31). In contrast, the enzymes of the type II FASs are all located on separate domains and are found in prokaryotes or in eukaryotic organelles of prokaryotic origin (33).Relatively common among eukaryotic organisms are the fatty acid elongase-based systems. These elongase-based systems directly elongate a fatty acyl chain esterfied with CoA (fatty acyl-CoA), which is in contrast to the type I and type II FAS systems, which elongate a fatty acyl chain attached to an acyl carrier protein. The elongase system is comprised of at least four enzymes that are responsible for adding two carbon units to the fatty acyl carboxyl end. The chemistry of this pathway is similar to that used by type I and type II FASs. Fatty acyl elongation begins with the condensation of malonyl-CoA with a fatty acyl-CoA catalyzed by the condensing enzyme LCE (␤-ketoacyl-CoA synthase) (Fig.

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Section: Resultssupporting

confidence: 68%

Cryptosporidium parvum Long-Chain Fatty Acid Elongase

2007

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“…Vertebrates have the most paralogs; for example, human and mouse have five paralogs, some of which have been experimentally confirmed to be involved in the elongation of PUFAs. Four of the seven sequences detected in protists have also proved to be elongases of PUFAs by a recent study (45). This subfamily also has one exception, which has been characterized as an elongase for short MUFAs in Drosophila melanogaster (46).…”

Section: Elongases Consist Of Two Functionally Distinct Subfamiliesmentioning

confidence: 99%

The repertoire of desaturases and elongases reveals fatty acid variations in 56 eukaryotic genomes

Hashimoto

Yoshizawa

Okuda

et al. 2008

Journal of Lipid Research

162

177

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The repertoire of biosynthetic enzymes found in an organism is an important clue for elucidating the chemical structural variations of various compounds. In the case of fatty acids, it is essential to examine key enzymes that are desaturases and elongases, whose combination determine the range of fatty acid structures. We systematically investigated 56 eukaryotic genomes to obtain 275 desaturase and 265 elongase homologs. Phylogenetic and motif analysis indicated that the desaturases consisted of four functionally distinct subfamilies and the elongases consisted of two subfamilies. From the combination of the subfamilies, we then predicted the ability to synthesize six types of fatty acids. Consequently, we found that the ranges of synthesizable fatty acids were often different even between closely related organisms. The reason is that, as well as diverging into subfamilies, the enzymes have functionally diverged within the individual subfamilies. Finally, we discuss how the adaptation to individual environments and the ability to synthesize specific metabolites provides some explanation for the diversity of enzyme functions. This study provides an example of a potent strategy to bridge the gap from genomic knowledge to chemical

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“…These organisms have unique endoplasmic reticulum (ER) based elongases (4). A few years ago the polyunsaturated FA synthesis pathway was completely revealed in trypanosomatids (5,6). Among the trypanosomatids, only Leishmania has the ability to convert C18:0 to arachidonate or to even larger and more unsaturated FAs (up to 22:6); therefore, this organism can synthesize all of the polyunsaturated FAs (PUFAs) it requires from stearate (6,7).…”

Section: Fatty Acid Desaturases (Fads)mentioning

confidence: 99%

“…A few years ago the polyunsaturated FA synthesis pathway was completely revealed in trypanosomatids (5,6). Among the trypanosomatids, only Leishmania has the ability to convert C18:0 to arachidonate or to even larger and more unsaturated FAs (up to 22:6); therefore, this organism can synthesize all of the polyunsaturated FAs (PUFAs) it requires from stearate (6,7). Trypanosomes have to take up precursors from the host to produce FAs beyond linoleate (18:2) as they apparently lack the desaturases that are required for processing linoleate further (7,8).…”

Section: Fatty Acid Desaturases (Fads)mentioning

confidence: 99%

NAD(P)H Cytochrome b5 Oxidoreductase Deficiency in Leishmania major Results in Impaired Linoleate Synthesis Followed by Increased Oxidative Stress and Cell Death

Mukherjee

Santara

Das

et al. 2012

Journal of Biological Chemistry

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Background: NAD(P)H cytochrome b 5 oxidoreductase (Ncb5or) participates in a variety of metabolic conversions. Results: A new Ncb5or acts as a redox partner of ⌬12 fatty acid desaturase. Conclusion: Ncb5or null mutant suffers from impaired linoleate synthesis leading to oxidative stress and cell death. Significance: Our results have exposed a novel fatty acid synthesis pathway in L. major that differs from the mammalian system.

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Elongation of polyunsaturated fatty acids in trypanosomatids

Cited by 39 publications

References 31 publications

Cryptosporidium parvum Long-Chain Fatty Acid Elongase

Cryptosporidium parvum Long-Chain Fatty Acid Elongase

The repertoire of desaturases and elongases reveals fatty acid variations in 56 eukaryotic genomes

NAD(P)H Cytochrome b5 Oxidoreductase Deficiency in Leishmania major Results in Impaired Linoleate Synthesis Followed by Increased Oxidative Stress and Cell Death

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