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J. Biol. Chem., Vol. 278, Issue 24, 22014-22022, June 13, 2003

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Multiple Splice Variants Encode a Novel Adenylyl Cyclase of Possible Plastid Origin Expressed in the Sexual Stage of the Malaria Parasite Plasmodium falciparum^*

David K. Muhia  , Claire A. Swales , Ursula Eckstein-Ludwig ¶, Shweta Saran ||, Spencer D. Polley , John M. Kelly , Pauline Schaap ||, Sanjeev Krishna ¶ and David A. Baker  **

From the Department of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, Keppel Street, London, WC1E 7HT, United Kingdom, ^¶ Department of Cellular and Molecular Medicine, St. George's Hospital Medical School, Cranmer Terrace, London, SW17 ORE, United Kingdom, ^|| Wellcome Trust Biocentre, Dow Street, University of Dundee, Dundee, DD1 5EH, United Kingdom

We report the characterization of an unusual adenylyl cyclase gene from Plasmodium falciparum, here designated PfAC. The level of mRNA expression is maximum during development of gametocytes (the sexual blood stage of the parasite life cycle). The gene is highly interrupted by 22 introns, and reverse transcriptase-PCR analysis revealed that there are multiple mRNA splice variants. One intron has three alternative 3'-splice sites that confer the potential to encode distinct forms of the enzyme using alternative start codons. Deduced amino acid sequences predict membrane-spanning regions, the number of which can vary between two and six depending on the splice variant. Expression of a synthetic form of two of these variants in Xenopus oocytes and in Dictyostelium adenylyl cyclase-deficient mutants, confirms that PfAC is a functional adenylyl cyclase. These results identify a novel mechanism in P. falciparum for the generation of multiple isoforms of a key, membrane-bound signaling molecule from a single genomic copy. Comparisons of the catalytic domains of PfAC and a second putative P. falciparum adenylyl cyclase (PfAC) with those from other species reveal an unexpected similarity with adenylyl cyclases from certain prokaryotes including the cyanobacteria (blue green algae). In addition, the presence of an unusual active site substitution in a position that determines substrate specificity, also characteristic of these prokaryotic forms of the enzyme, further suggests a plastid origin for the Plasmodium cyclases.

Received for publication, February 17, 2003 , and in revised form, March 25, 2003.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AY191005.

^* This work was supported by the Wellcome Trust, Wellcome Trust University Award Ref 058038 (to D. B.), Wellcome Trust Prize Fellowship Ref 062531 (to D. M.), and Wellcome Trust University Award Ref 057137 (to P. S. and supporting S. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Present address: Molecular Parasitology Group, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Headington, Oxford OX3 9DS, UK.

^** To whom correspondence should be addressed. Fax: 44-207-636-8739; E-mail: david.baker{at}lshtm.ac.uk.

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