Abstract
We present a systems biology view on pseudoenzymes that acknowledges that genes are not selfish: the genome is. With network function as the selectable unit, there has been an evolutionary bonus for recombination of functions of and within proteins. Many proteins house a functionality by which they 'read' the cell's state, and one by which they 'write' and thereby change that state. Should the writer domain lose its cognate function, a 'pseudoenzyme' or 'pseudosignaler' arises. GlnK involved in Escherichia coli ammonia assimilation may well be a pseudosignaler, associating 'reading' the nitrogen state of the cell to 'writing' the ammonium uptake activity. We identify functional pseudosignalers in the cyclin-dependent kinase complexes regulating cell-cycle progression. For the mitogen-activated protein kinase pathway, we illustrate how a 'dead' pseudosignaler could produce potentially selectable functionalities. Four billion years ago, bioenergetics may have shuffled 'electron-writers', producing various networks that all served the same function of anaerobic ATP synthesis and carbon assimilation from hydrogen and carbon dioxide, but at different ATP/acetate ratios. This would have enabled organisms to deal with variable challenges of energy need and substrate supply. The same principle might enable 'gear-shifting' in real time, by dynamically generating different pseudo-redox enzymes, reshuffling their coenzymes, and rerouting network fluxes. Non-stationary pH gradients in thermal vents together with similar such shuffling mechanisms may have produced a first selectable proton-motivated pyrophosphate synthase and subsequent ATP synthase. A combination of functionalities into enzymes, signalers, and the pseudoversions thereof may offer fitness in terms of plasticity, both in real time and in evolution.