Why a "benign" mutation kills enzyme activity. Structure-based analysis of the A176V mutant of Saccharomyces cerevisiae L-asparaginase I.
A conservative and apparently harmless A176V mutation in intracellular S. cerevisiae L-asparaginase (ScerAI) completely abolishes the enzyme activity. Sequence and structural comparisons with type II bacterial L-asparaginases show that the mutated residue is in a very conservative region and plays a vital role in the cohesion of functional tetramers of these enzymes through participation in side-chain...main-chain (Ser) Oy...O (Ala) hydrogen bonds across the tetramer interface. The fact that bacterial L-asparaginases of type I show less conservation in this region suggests that they may have different quaternary structure while adopting the subunit fold and intimate dimer architecture of type II enzymes. A comparison of all available sequences of microbial L-asparaginases confirms that separate intra- and extra-cellular enzymes evolved in prokaryotes and eukaryotes independently. However, an analysis of the available complete genome sequences reveals a surprising fact that Haemophilus influenzae possesses only a type II asparaginase while the archaebacterium Methanococcus jannaschii has a type I gene, but not a type II.
Bonthron
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DT
Human Genetics Unit, University of Edinburgh, Western General Hospital, UK.
Jaskólski
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M
D000595:Amino Acid Sequence; D001215:Asparaginase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D012441:Saccharomyces cerevisiae / Q000201:enzymology* / Q000235:genetics; D017386:Sequence Homology, Amino Acid
D001215:Asparaginase