Two pathways for cysteine biosynthesis in Leishmania major

Roderick A.M. Williams, Gareth D. Westrop, G.H. Coombs

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

Genome mining and biochemical analyses have shown that Leishmania major possesses two pathways for cysteine synthesis - the de novo biosynthesis pathway comprising SAT (serine acetyltransferase) and CS (cysteine synthase) and the RTS (reverse trans-sulfuration) pathway comprising CBS (cystathionine β-synthase) and CGL (cystathionine γ-lyase). The LmjCS (L. major CS) is similar to the type A CSs of bacteria and catalyses the synthesis of cysteine using O-acetylserine and sulfide with Kms of 17.5 and 0.13 mM respectively. LmjCS can use sulfide provided by the action of MST (mercaptopyruvate sulfurtransferase) on 3-MP (3-mercaptopyruvate). LmjCS forms a bi-enzyme complex with Leishmania SAT (and Arabidopsis SAT), with residues Lys222, His226 and Lys227 of LmjCS being involved in the complex formation. LmjCBS (L. major CBS) catalyses the synthesis of cystathionine from homocysteine, but, unlike mammalian CBS, also has high cysteine synthase activity (but with the Km for sulfide being 10.7 mM). In contrast, LmjCS does not have CBS activity. CS was up-regulated when promastigotes were grown in medium with limited availability of sulfur amino acids. Exogenous methionine stimulated growth under these conditions and also the levels of intracellular cysteine, glutathione and trypanothione, whereas cysteine had no effect on growth or the intracellular cysteine levels, correlating with the low rate of transport of cysteine into the cell. These results suggest that cysteine is generated endogenously by promastigotes of Leishmania. The absence of CS from mammals and the clear differences between CBS of mammals and Leishmania suggest that each of the parasite enzymes could be a viable drug target.
LanguageEnglish
Pages451-462
Number of pages11
JournalBiochemical Journal
Volume420
DOIs
Publication statusPublished - Mar 2009

Fingerprint

Leishmania major
Cysteine Synthase
Biosynthesis
Cysteine
Serine O-Acetyltransferase
Leishmania
Sulfides
Mammals
Cystathionine gamma-Lyase
Cystathionine
Cystathionine beta-Synthase
Sulfur Amino Acids
Homocysteine
Enzymes
Growth
Arabidopsis
Methionine
Glutathione
Bacteria
Parasites

Keywords

  • cysteine biosynthesis
  • ysteine synthase
  • cystathionine β-synthase
  • leishmania
  • protozoan parasite

Cite this

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abstract = "Genome mining and biochemical analyses have shown that Leishmania major possesses two pathways for cysteine synthesis - the de novo biosynthesis pathway comprising SAT (serine acetyltransferase) and CS (cysteine synthase) and the RTS (reverse trans-sulfuration) pathway comprising CBS (cystathionine β-synthase) and CGL (cystathionine γ-lyase). The LmjCS (L. major CS) is similar to the type A CSs of bacteria and catalyses the synthesis of cysteine using O-acetylserine and sulfide with Kms of 17.5 and 0.13 mM respectively. LmjCS can use sulfide provided by the action of MST (mercaptopyruvate sulfurtransferase) on 3-MP (3-mercaptopyruvate). LmjCS forms a bi-enzyme complex with Leishmania SAT (and Arabidopsis SAT), with residues Lys222, His226 and Lys227 of LmjCS being involved in the complex formation. LmjCBS (L. major CBS) catalyses the synthesis of cystathionine from homocysteine, but, unlike mammalian CBS, also has high cysteine synthase activity (but with the Km for sulfide being 10.7 mM). In contrast, LmjCS does not have CBS activity. CS was up-regulated when promastigotes were grown in medium with limited availability of sulfur amino acids. Exogenous methionine stimulated growth under these conditions and also the levels of intracellular cysteine, glutathione and trypanothione, whereas cysteine had no effect on growth or the intracellular cysteine levels, correlating with the low rate of transport of cysteine into the cell. These results suggest that cysteine is generated endogenously by promastigotes of Leishmania. The absence of CS from mammals and the clear differences between CBS of mammals and Leishmania suggest that each of the parasite enzymes could be a viable drug target.",
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Two pathways for cysteine biosynthesis in Leishmania major. / Williams, Roderick A.M.; Westrop, Gareth D.; Coombs, G.H.

In: Biochemical Journal, Vol. 420, 03.2009, p. 451-462.

Research output: Contribution to journalArticle

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