Abstract
About 1 billion years ago, in a single-celled holozoan ancestor of all animals, a gene fusion of two tRNA synthetases formed the bifunctional enzyme, glutamyl-prolyl-tRNA synthetase (EPRS). We propose here that a confluence of metabolic, biochemical, and environmental factors contributed to the specific fusion of glutamyl- (ERS) and prolyl- (PRS) tRNA synthetases. To test this idea, we developed a mathematical model that centers on the precursor-product relationship of glutamic acid and proline, as well as metabolic constraints on free glutamic acid availability near the time of the fusion event. Our findings indicate that proline content increased in the proteome during the emergence of animals, thereby increasing demand for free proline. Together, these constraints contributed to a marked cellular depletion of glutamic acid and its products, with potentially catastrophic consequences. In response, an ancient organism invented an elegant solution in which genes encoding ERS and PRS fused to form EPRS, forcing coexpression of the two enzymes and preventing lethal dysregulation. The substantial evolutionary advantage of this coregulatory mechanism is evidenced by the persistence of EPRS in nearly all extant animals.
Highlights
About 1 billion years ago, in a single-celled holozoan ancestor of all animals, a gene fusion of two tRNA synthetases formed the bifunctional enzyme, glutamyl-prolyl-tRNA synthetase (EPRS)
Proline can be generated from ornithine; ornithine is derived from arginine, which in turn is derived from glutamic acid [19, 20]
The synthesis of proline from glutamic acid is inhibited by proline-mediated negative feedback of pyroline-5-carboxylate reductase [21, 22]
Summary
Opisthokont after the divergence from fungi about 1 billion years ago [11] (see Fig. 1). We considered the possibility that a fused EPRS was required for structural integrity of the MSC. Small complexes of two to four ARSs are present in some archaea, trypanosomes, and fungi, all organisms lacking fused EPRS [17]. Through a gradual process of accretion and occasional deletion of specific ARSs, a “mega” MSC consisting of eight or more ARSs (plus noncatalytic auxiliary proteins) appeared at about the same time as the linkage of ERS and PRS in metazoan animals or their unicellular animal-like ancestors (Fig. 1). The large MSC in C. elegans containing eight ARSs, including ERS but not PRS, suggests that a fused EPRS is not essential for MSC formation or integrity [18]. A putative requirement for EPRS in structural integrity of the MSC does not clarify the specific selection of this ARS pair for the fusion.
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