Abstract
BackgroundSelection pressure governs the relative mutability and the conservedness of a protein across the protein family. Biomolecules (DNA, RNA and proteins) continuously evolve under the effect of evolutionary pressure that arises as a consequence of the host parasite interaction. IPCS (Inositol phosphorylceramide synthase), SPL (Sphingosine-1-P lyase) and SPT (Serine palmitoyl transferase) represent three important enzymes involved in the sphingolipid metabolism of Leishmania. These enzymes are responsible for maintaining the viability and infectivity of the parasite and have been classified as druggable targets in the parasite metabolome.ResultsThe present work relates to the role of selection pressure deciding functional conservedness and divergence of the drug targets. IPCS and SPL protein families appear to diverge from the SPT family. The three protein families were largely under the influence of purifying selection and were moderately conserved baring two residues in the IPCS protein which were under the influence of positive selection. To further explore the selection pressure at the codon level, codon usage bias indices were calculated to analyze genes for their synonymous codon usage pattern. IPCS gene exhibited slightly lower codon bias as compared to SPL and SPT protein families.ConclusionEvolutionary tracing of the proposed drug targets has been done with a viewpoint that the amino-acids lining the drug binding pocket should have a lower evolvability. Sites under positive selection (HIS20 and CYS30 of IPCS) should be avoided during devising strategies for inhibitor design.
Highlights
Selection pressure governs the relative mutability and the conservedness of a protein across the protein family
There is no mammalian equivalent of this enzyme and thereby Inositol phosphoryl ceramide synthase (IPCS) has been considered as an attractive drug target in the sphingolipid metabolism of Leishmania [7]
It was observed that IPCS and Sphingosine 1-P-lyase (SPL) protein families were phylogenetically distant from SPT protein family
Summary
Selection pressure governs the relative mutability and the conservedness of a protein across the protein family. IPCS (Inositol phosphorylceramide synthase), SPL (Sphingosine-1-P lyase) and SPT (Serine palmitoyl transferase) represent three important enzymes involved in the sphingolipid metabolism of Leishmania. These enzymes are responsible for maintaining the viability and infectivity of the parasite and have been classified as druggable targets in the parasite metabolome. Sphingolipids form an integral component of the parasitic membranes [1] They are localized in the membrane micro domains and are SPT, the first key enzyme in the sphingolipid metabolism localizes into the endoplasmic reticulum and belongs to the class-II pyridoxal-phosphate-dependent aminotransferase family [4].
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