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  • Review Article
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A fatty-acid synthesis mechanism specialized for parasitism

Nature Reviews Microbiology volume 5, pages 287–297 (2007)Cite this article

Key Points

  • Trypanosoma brucei, T. cruzi and Leishmania spp. parasites are early branching eukaryotes that cause disease mainly in tropical countries. T. brucei synthesizes fatty acids (FAs) de novo. While bloodstream forms make myristate (C14) for glycosylphosphatidylinositol (GPI) anchors of their variant surface glycoprotein (which mediate antigenic variation), procyclic forms make mainly stearate (C18).

  • Rather than a conventional type I or II FA synthase, T. brucei uses a coenzyme A (CoA)-dependent microsomal FA elongase (ELO) pathway for most of its de novo synthesis. In other eukaryotes, the ELO pathway simply lengthens already long fatty acyl-CoAs. The T. brucei mitochondrial type II synthase is more specialized and makes octanoate (C8), a lipoic-acid precursor, as well as longer FAs up to C16.

  • While TbELO1–3 elongate C4 primer to C18, TbELO4 functions as a polyunsaturated FA ELO that lengthens arachidonate (C20:4) salvaged from the host. In addition to TbELO1–4 orthologues, L. major has desaturases and an extra polyunsaturated FA (PUFA) ELO needed to synthesize C22:5n-6 and C22:6n-3 from C18. By contrast, the two trypanosomes seem to have lost the portion of their PUFA pathway that converts 18:2n-6 to 20:4n-6 and 20:5n-3.

  • T. cruzi and Leishmania spp. have additional TbELO1–3 homologues that are probably involved in synthesis of the very-long-chain saturated acyl and alkyl groups that are found on surface GPI anchors and glycoconjugates. These GPIs, depending on the fatty chain length and degree of saturation, are involved in immunity and inflammation in different life-cycle stages. The selective regulation of the various ELOs could explain how these parasites produce the various FAs needed during different life-cycle stages, as happens in T. brucei.

  • Other eukaryotic parasitic protozoans such as the mucosal parasites and apicomplexans use mechanisms apparently dissimilar to those in trypanosomatids to make or acquire their bulk FAs.

  • Trypanosomatid mitochondrial type II and ELO pathways are apparently essential for parasite survival and could serve as potential drug targets.

  • The ELO pathway seems to have evolved to accommodate the complex and parasitic life-style of the trypanosomatids, allowing it to produce the different FAs that are needed as it migrates between different compartments in the vector and host.

Abstract

Most cells use either a type I or type II synthase to make fatty acids. Trypanosoma brucei, the sleeping sickness parasite, provides the first example of a third mechanism for this process. Trypanosomes use microsomal elongases to synthesize fatty acids de novo, whereas other cells use elongases to make long-chain fatty acids even longer. The modular nature of the pathway allows synthesis of different fatty-acid end products, which have important roles in trypanosome biology. Indeed, this newly discovered mechanism seems ideally suited for the parasitic lifestyle.

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Figure 1: Trypanosoma brucei organelles and fatty-acid-related pathways.
Figure 2: Life cycle of Trypanosoma brucei.
Figure 3: Enzymology of the elongase (ELO) pathway.
Figure 4: Phylogenetic tree of trypanosomatid, apicomplexan and yeast elongases (ELOs).

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Acknowledgements

We would like to thank S. Beverley, R. Gazzinelli, D. Hanasekaran, J. Lukes, Y. Morita, K. Paul, J. Pevsner, S. Prigge, D. Roos, J. Samuelson and S. Subramanian for discussions. We would also like to thank R. Gazzinelli and A. Uttaro for sharing unpublished manuscripts. We are grateful to G. Yildirir and other members of our laboratory for support. Work in the authors' laboratory has been supported by a grant from the US National Institutes of Health.

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Authors and Affiliations

  1. Department of Biological Chemistry, Johns Hopkins School of Medicine, 725 North Wolfe Street, Baltimore, 21205, Maryland, USA

    Soo Hee Lee, Jennifer L. Stephens & Paul T. Englund

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  1. Soo Hee Lee
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  2. Jennifer L. Stephens
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  3. Paul T. Englund
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Correspondence to Paul T. Englund.

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Related links

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DATABASES

Entrez protein 

CAJ02037

CAJ02963

CAJ02967

CAJ02975

CAJ02982

CAJ02986

CAJ03003

CAJ03006

CAJ03013

CAJ03016

CAJ03023

CAJ03028

CAJ03035

CAJ08636

NP_009963

NP_012339

NP_013476

NP_703294

NP_704739

XP_808770

XP_809644

XP_813970

XP_813971

XP_813972

XP_966049

Saccharomyces genome database 

AYR1

ELO1

ELO2

ELO3

TSC13

YBR159W

ToxoDB 

20.m00392

52.m01617

49.m03288

FURTHER INFORMATION

Chagas' disease

GeneDB: Trypanosoma brucei genome

GiardiaDB

Leishmaniasis

Sleeping sickness

The Englund Laboratory

TIGR Database: Entamoeba histolytica Genome Project

TIGR Database: Toxoplasma gondii Genome Project

TIGR Database: Trichomonas vaginlis Genome Project

Glossary

Glycosome

An organelle, related to peroxisomes, found in trypanosomatid protozoans that contain enzymes of the glycolytic and other metabolic pathways.

Glycosylphosphatidylinositol

(GPI). A glycolipid, covalently linked to the C terminus of many eukaryotic proteins, which anchors them to the plasma membrane. Some polysaccharides, such as lipophosphoglycan (LPG) in Leishmania spp., are also GPI anchored.

Primer

A short, pre-existing acyl group that initiates chain growth in FA synthesis.

Phosphopantetheine

A component of CoA or a prosthetic group of ACP; during FA synthesis the growing acyl chain is thioesterified to the phosphopantetheine sulphydryl group.

HXXH amino-acid motif

A sequence, composed of two histidines (H) and two non-conserved amino acids (X), that is found in FA ELOs.

Epimastigote, promastigote and trypomastigote

Life-cycle stages of trypanosomatid protozoans that differ morphologically in the positioning of the flagellum.

Jaccard clustering

An algorithm for grouping highly related proteins.

Ceramide

A molecule composed of sphingosine and an FA that forms the lipid moiety of some GPI anchors and the phospholipid sphingomyelin.

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Lee, S., Stephens, J. & Englund, P. A fatty-acid synthesis mechanism specialized for parasitism. Nat Rev Microbiol 5, 287–297 (2007). https://doi.org/10.1038/nrmicro1617

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