Abstract
Promiscuity, the ability of an enzyme to catalyze diverse activities using the same active site, sets up the stage for the evolution of complex organisms through gene duplication and specialization. The detection of promiscuous motifs is crucial to understand the physiological relevance of a protein, or for any endeavor that intends to rationally modify these latent capabilities to design new proteins under laboratory conditions. We have established a methodology for identifying catalytic residues based on spatial and electrostatic congruence with known active site configurations. Here, we discuss insights gained in several initiatives using our method on different enzymes.
Highlights
Primitive life presumably had minimal gene content and a minuscule arsenal of enzymes at its disposal
Compound promiscuity plays a major role in drug discovery, and in the therapeutic efficacy of drugs[8]
We have demonstrated that such a structural conservation leading to the same function necessitates the conservation of electrostatic properties as well (CLASP www.sanchak.com/clasp)[32]
Summary
Primitive life presumably had minimal gene content and a minuscule arsenal of enzymes at its disposal. The complete motif was missing - stated previously as, ‘While Ser[195], His[57], and Gly[193] from the input motif have a highly matching scaffold in P14a, the spatial position of the elastase Asp[102] is close to Asn[35] and Ser[39] in P14a when the proteins are superimposed based on the matching scaffolds48’ - the structural similarity of the P14a protein to a snake venom protein with a known elastase function[50] suggested strongly the possibility of pre-existing elastase functionality, or indicated a fair chance of endowing elastase activity through directed evolution techniques Another fascinating aspect of enzymes, strictly not defined as promiscuity, is their ability to catalyze the reaction of a range of similar substrates of the same class[51]. Grant information The author(s) declared that no grants were involved in supporting this work
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