Managing enzyme promiscuity in plant specialized metabolism: A lesson from flavonoid biosynthesis

Abstract

Specificities of enzymes involved in plant specialized metabolism, including flavonoid biosynthesis, are generally promiscuous. This enzyme promiscuity has served as an evolutionary basis for new enzyme functions and metabolic pathways in land plants adapting to environmental challenges. This phenomenon may lead, however, to inefficiency in specialized metabolism and adversely affect metabolite‐mediated plant survival. How plants manage enzyme promiscuity for efficient specialized metabolism is, thus, an open question. Recent studies of flavonoid biosynthesis addressing this issue have revealed a conserved strategy, namely, a homolog of chalcone isomerase with no catalytic activity binds to chalcone synthase, a key flavonoid pathway enzyme, to narrow (or rectify) the enzyme's highly promiscuous product specificity. Reducing promiscuity via specific protein–protein interactions among metabolic enzymes and proteins may be a solution adopted by land plants to achieve efficient operation of specialized metabolism, while the intrinsic promiscuity of enzymes has likely been retained incidentally.

Redesigning plant specialized metabolism with supervised machine learning using publicly available reactome data

“…On the other hand, using the highest possible promiscuity threshold ( d = 2) to extract reaction rules for use in retrobiosynthesis will result in an astronomical search space that is too large to evaluate computationally. Additionally, it is not intuitive to use a single blanket threshold to extract reaction rules across all enzymatic reactions as enzymes of different classes have been known to possess varying degrees of promiscuity [26] , [24] , [121] .…”

“…Enzyme promiscuity can be useful to redesign biosynthetic pathways. Briefly, promiscuous enzymes can accept different substrates (substrate promiscuity) [21] , generate different products from the same substrate (product promiscuity) [22] and catalyze different reactions depending on the substrate (catalytic promiscuity) [23] , [24] . This promiscuity can be leveraged to produce novel compounds [25] , [26] , [27] and thus, allows for the exploration of new biosynthetic routes for valuable specialized metabolites using retrobiosynthetic approaches [28] .…”

KIPEs3: Automatic annotation of biosynthesis pathways

“…This requires specific attention when interpreting the KIPEs3 results to avoid false positives. While the aglycon biosynthesis is highly conserved and catalyzed by well characterized enzymes, flavonoid decorating enzymes are less studied and show a high level of promiscuity [70][71][72]. This poses a challenge for the identification through sequence similarity.…”

Origin and Function of Structural Diversity in the Plant Specialized Metabolome

“…They have lower k cat values (the turnover number) and a broader substrate specificity, meaning that they catalyze the same reaction at similar, relatively low, rates on multiple substrates [15,147]. If the different substrates for low substrate specific enzymes are available, this may result in pathways with a grid-like structure, as is commonly seen in the biosynthesis pathways of the core skeletons of specialized metabolites, including monolignols, flavonoids, oxylipins and brassinosteroids [148,149]. Poor substrate specificity of modifying, rather than the core-pathway enzymes, may contribute extensively to structural diversity, depending on the availability and compartmentation of the substrates.…”