Plasmodium falciparum: asparagine mutant at residue 108 of dihydrofolate reductase is an optimal antifolate-resistant single mutant.

Abstract:

:The codon for serine residue 108 of the Plasmodium falciparum dihydrofolate reductase gene was replaced with those for the other 19 amino acids. Except for the Lys108 mutant, which was not expressed, all other substitutions yielded DHFR mutants which were expressed in Escherichia coli as inactive inclusion bodies. Nine of the mutants--Asn108, Thr108, Gly108, Ala108, Gln108, Cys108, Val108, Leu108, and Met108--yielded active DHFR upon refolding of the protein from the inclusion bodies. The remaining mutants--IIe108, Arg108, Pro108, Asp108, His108, Tyr108, Phe108, Trp108, and Glu108--did not exhibit detectable DHFR activity on refolding. The Asn108 mutant had almost unperturbed kinetic parameters but conferred resistance to pyrimethamine and cycloguanil; other active mutants showed poorer DHFR activity. We purified and characterized four mutants which produced highest DHFR activity, i.e., the Gln108, Gly108, Cys108, and Ala108 mutants. These mutant enzymes had kcat/K(m) values ranging from 7 to 22% of the wild-type enzyme. While DHFRs from Gly108, Cys108, and Ala108 mutants were as susceptible to pyrimethamine and cycloguanil as the wild type, the Gln108 mutation conferred high resistance to both inhibitors. Our data suggest that residue 108 is important for antifolate binding, and that the Ser108 to Asn108 mutation was selected in nature because of (i) the need for only a single base change, (ii) its good activity, and (iii) its resistance to antifolates.

journal_name

Exp Parasitol

authors

Sirawaraporn W,Yongkiettrakul S,Sirawaraporn R,Yuthavong Y,Santi DV

doi

10.1006/expr.1997.4221

subject

Has Abstract

pub_date

1997-11-01 00:00:00

pages

245-52

issue

3

eissn

0014-4894

issn

1090-2449

pii

S0014-4894(97)94221-1

journal_volume

87

pub_type

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