• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of biochemjBJ Latest papers and much more!
Biochem J. Oct 15, 2002; 367(Pt 2): 321–327.
PMCID: PMC1222900

Involvement of delta-aminolaevulinate synthase encoded by the parasite gene in de novo haem synthesis by Plasmodium falciparum.


The malaria parasite can synthesize haem de novo. In the present study, the expression of the parasite gene for delta-aminolaevulinate synthase (Pf ALAS ) has been studied by reverse transcriptase PCR analysis of the mRNA, protein expression using antibodies to the recombinant protein expressed in Escherichia coli and assay of ALAS enzyme activity in Plasmodium falciparum in culture. The gene is expressed through all stages of intra-erythrocytic parasite growth, with a small increase during the trophozoite stage. Antibodies to the erythrocyte ALAS do not cross-react with the parasite enzyme and vice versa. The recombinant enzyme activity is inhibited by ethanolamine and the latter inhibits haem synthesis in P. falciparum and growth in culture. The parasite ALAS is localized in the mitochondrion and its import into mitochondria in a cell-free import assay has been demonstrated. The import is blocked by haemin. On the basis of these results, the following conclusions are arrived at: PfALAS has distinct immunological identity and inhibitor specificity and is therefore a drug target. The malaria parasite synthesizes haem through the mitochondrion/cytosol partnership, and this assumes significance in light of the presence of apicoplasts in the parasite that may be capable of independent haem synthesis. The Pf ALAS gene is functional and vital for parasite haem synthesis and parasite survival.

Full Text

The Full Text of this article is available as a PDF (248K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Surolia N, Padmanaban G. de novo biosynthesis of heme offers a new chemotherapeutic target in the human malarial parasite. Biochem Biophys Res Commun. 1992 Sep 16;187(2):744–750. [PubMed]
  • Bonday ZQ, Taketani S, Gupta PD, Padmanaban G. Heme biosynthesis by the malarial parasite. Import of delta-aminolevulinate dehydrase from the host red cell. J Biol Chem. 1997 Aug 29;272(35):21839–21846. [PubMed]
  • Wilson CM, Smith AB, Baylon RV. Characterization of the delta-aminolevulinate synthase gene homologue in P. falciparum. Mol Biochem Parasitol. 1996 Jan;75(2):271–276. [PubMed]
  • Lathrop JT, Timko MP. Regulation by heme of mitochondrial protein transport through a conserved amino acid motif. Science. 1993 Jan 22;259(5094):522–525. [PubMed]
  • Trager W, Jensen JB. Human malaria parasites in continuous culture. Science. 1976 Aug 20;193(4254):673–675. [PubMed]
  • Lambros C, Vanderberg JP. Synchronization of Plasmodium falciparum erythrocytic stages in culture. J Parasitol. 1979 Jun;65(3):418–420. [PubMed]
  • Fitch CD, Chevli R, Banyal HS, Phillips G, Pfaller MA, Krogstad DJ. Lysis of Plasmodium falciparum by ferriprotoporphyrin IX and a chloroquine-ferriprotoporphyrin IX complex. Antimicrob Agents Chemother. 1982 May;21(5):819–822. [PMC free article] [PubMed]
  • Baca AM, Hol WG. Overcoming codon bias: a method for high-level overexpression of Plasmodium and other AT-rich parasite genes in Escherichia coli. Int J Parasitol. 2000 Feb;30(2):113–118. [PubMed]
  • MAUZERALL D, GRANICK S. The occurrence and determination of delta-amino-levulinic acid and porphobilinogen in urine. J Biol Chem. 1956 Mar;219(1):435–446. [PubMed]
  • Gardner LC, Smith SJ, Cox TM. Biosynthesis of delta-aminolevulinic acid and the regulation of heme formation by immature erythroid cells in man. J Biol Chem. 1991 Nov 15;266(32):22010–22018. [PubMed]
  • Chen LB. Fluorescent labeling of mitochondria. Methods Cell Biol. 1989;29:103–123. [PubMed]
  • Das A, Syin C, Fujioka H, Zheng H, Goldman N, Aikawa M, Kumar N. Molecular characterization and ultrastructural localization of Plasmodium falciparum Hsp 60. Mol Biochem Parasitol. 1997 Sep;88(1-2):95–104. [PubMed]
  • Söllner T, Rassow J, Pfanner N. Analysis of mitochondrial protein import using translocation intermediates and specific antibodies. Methods Cell Biol. 1991;34:345–358. [PubMed]
  • Jascur T. Import of precursor proteins into yeast submitochondrial particles. Methods Cell Biol. 1991;34:359–368. [PubMed]
  • Ferreira GC, Dailey HA. Expression of mammalian 5-aminolevulinate synthase in Escherichia coli. Overproduction, purification, and characterization. J Biol Chem. 1993 Jan 5;268(1):584–590. [PubMed]
  • MATTHEW M, NEUBERGER A. Aminomalonate as an enzyme inhibitor. Biochem J. 1963 Jun;87:601–612. [PMC free article] [PubMed]
  • Nakakuki M, Yamauchi K, Hayashi N, Kikuchi G. Purification and some properties of delta-aminolevulinate synthase from the rat liver cytosol fraction and immunochemical identity of the cytosolic enzyme and the mitochondrial enzyme. J Biol Chem. 1980 Feb 25;255(4):1738–1745. [PubMed]
  • Bonday ZQ, Dhanasekaran S, Rangarajan PN, Padmanaban G. Import of host delta-aminolevulinate dehydratase into the malarial parasite: identification of a new drug target. Nat Med. 2000 Aug;6(8):898–903. [PubMed]
  • Sato S, Tews I, Wilson RJ. Impact of a plastid-bearing endocytobiont on apicomplexan genomes. Int J Parasitol. 2000 Apr 10;30(4):427–439. [PubMed]
  • Sato Shigeharu, Wilson RJM. The genome of Plasmodium falciparum encodes an active delta-aminolevulinic acid dehydratase. Curr Genet. 2002 Mar;40(6):391–398. [PubMed]
  • Waller RF, Keeling PJ, Donald RG, Striepen B, Handman E, Lang-Unnasch N, Cowman AF, Besra GS, Roos DS, McFadden GI. Nuclear-encoded proteins target to the plastid in Toxoplasma gondii and Plasmodium falciparum. Proc Natl Acad Sci U S A. 1998 Oct 13;95(21):12352–12357. [PMC free article] [PubMed]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...