Roy Jensen in 1976 theorised that primordial enzymes had to be highly promiscuous in order for
metabolic networks to assemble in a patchwork fashion (hence its name, the patchwork model).
This primordial catalytic versatility was later lost in favour of highly catalytic specialised
orthologous enzymes. As a consequence, many central-metabolic enzymes have structural
homologues that diverged before the last universal common ancestor.
Promiscuity is however not only a primordial trait, in fact it is very widespread property
in modern genomes. A series of experiments have been conducted to assess the distribution of
promiscuous enzyme activities in E. coli. In E. coli 21 out of 104 single-gene knockouts tested
(from the Keio collection) could be rescued by overexpressing a noncognate E. coli The
mechanisms by which the noncognate ORF could rescue the knockout can be grouped into eight
categories: isozyme overexpression (homologues), substrate ambiguity, transport ambiguity
(scavenging), catalytic promiscuity, metabolic flux maintenance (including overexpression of the
large component of a synthase in the absence of the amine transferase subunit), pathway bypass,
regulatory effects and unknown mechanisms Similarly, overexpressing the ORF collection
allowed E. coli to gain over an order of magnitude in resistance in 86 out 237 toxic environment.
Homologues are sometimes known to display promiscuity towards each other's main
reactions. This crosswise promiscuity was been most studied with members of the Alkaline
phosphatase superfamily, which catalyse hydrolytic reaction on the sulfate, phosphonate,
monophoshate, diphosphate or triphosphate ester bond of several compounds. despite the
divergence the homologues have a varying degree of reciprocal promiscuity: the difference in
promiscuity are due mechanisms involved, particularly the intermediate required.
Enzymes are generally in a state that is not only a compromise between stability and catalytic
efficiency, but also for specificity and evolvability, the latter two dictating whether an enzyme is
a generalist (highly evolvable due to large promiscuity, but low main activity) or a specialist
(high main activity, poorly evolvable due to low promiscuity). Examples of these are enzyme for
primary and secondary metabolism in plants (§ Plant secondary metabolism below). Other
factors can come into play, for example the glycerophosphodiesterase (gpdQ) from Enterobacter
aerogenes shows different values for its promiscuous activities depending on the two metal ions
it binds, which is dictated by ion availability. In some case promiscuity can be increased by
relaxing the specificity of the active site by enlarging it with a single mutation as was the case of
a D297G mutant of the E. coli L-Ala-D/L-Glu epimerase (ycjG) and E323G mutant of a
pseudomonad muconate lactonizing enzyme II