A Bird’s-Eye View of Enzyme Evolution: Chemical, Physicochemical, and Physiological Considerations

Abstract

Enzymes catalyze a vast range of reactions. Their catalytic performances, mechanisms, global folds, and active-site architectures are also highly diverse, suggesting that enzymes are shaped by an entire range of physiological demands and evolutionary constraints, as well as by chemical and physicochemical constraints. We have attempted to identify signatures of these shaping demands and constraints. To this end, we describe a bird's-eye view of the enzyme space from two angles: evolution and chemistry. We examine various chemical reaction parameters that may have shaped the catalytic performances and active-site architectures of enzymes. We test and weigh these considerations against physiological and evolutionary factors. Although the catalytic properties of the "average" enzyme correlate with cellular metabolic demands and enzyme expression levels, at the level of individual enzymes, a multitude of physiological demands and constraints, combined with the coincidental nature of evolutionary processes, result in a complex picture. Indeed, neither reaction type (a chemical constraint) nor evolutionary origin alone can explain enzyme rates. Nevertheless, chemical constraints are apparent in the convergence of active-site architectures in independently evolved enzymes, although significant variations within an architecture are common.

Machine learning applied to enzyme turnover numbers reveals protein structural correlates and improves metabolic models

“…3 ). This minor role of catalytic mechanism in comparison to evolutionary factors is supported by a recent analysis of in vitro k cat s in the context of spontaneous reaction rates 41 . Interestingly, the Michaelis constant ( K m ) is a very important feature in the model for k cat in vitro, but plays no significant role in the k app,max model.…”

Highly active rubiscos discovered by systematic interrogation of natural sequence diversity

“…The assembled k cat values suggest that rubisco is a kinetically constrained enzyme. First, the median measured k cat value is 3.3 s À1 , threefold slower than the median enzyme (Bar-Even et al, 2011;Davidi et al, 2018). Second, despite being so overrepresented in kinetic studies, rubisco's k cat values span the smallest dynamic range across all catalytically characterized enzymes (Flamholz et al, 2019).…”

Mimochrome, a metalloporphyrin‐based catalytic Swiss knife†

“…Nature has been able to bow kinetics and thermodynamics to make life not only possible but also predominant on Earth. We have learned, through the study of an exponentially growing number of biological structures, that this was accomplished by selecting only few elements [1][2][3][4], few molecules [5][6][7], and even few repetitive folding motifs [8][9][10][11][12][13]. This last aspect may appear surprising at a first glance, but it actually sounds pretty comfortable to chemists, who learned over centuries that the synthesis and/or functionalization of analogues from a starting framework moiety is advantageous and generally affordable, both in terms of synthetic pathway and economic cost.…”