Non-homologous isofunctional enzymes: A systematic analysis of alternative solutions in enzyme evolution

Abstract

BackgroundEvolutionarily unrelated proteins that catalyze the same biochemical reactions are often referred to as analogous - as opposed to homologous - enzymes. The existence of numerous alternative, non-homologous enzyme isoforms presents an interesting evolutionary problem; it also complicates genome-based reconstruction of the metabolic pathways in a variety of organisms. In 1998, a systematic search for analogous enzymes resulted in the identification of 105 Enzyme Commission (EC) numbers that included two or more proteins without detectable sequence similarity to each other, including 34 EC nodes where proteins were known (or predicted) to have distinct structural folds, indicating independent evolutionary origins. In the past 12 years, many putative non-homologous isofunctional enzymes were identified in newly sequenced genomes. In addition, efforts in structural genomics resulted in a vastly improved structural coverage of proteomes, providing for definitive assessment of (non)homologous relationships between proteins.ResultsWe report the results of a comprehensive search for non-homologous isofunctional enzymes (NISE) that yielded 185 EC nodes with two or more experimentally characterized - or predicted - structurally unrelated proteins. Of these NISE sets, only 74 were from the original 1998 list. Structural assignments of the NISE show over-representation of proteins with the TIM barrel fold and the nucleotide-binding Rossmann fold. From the functional perspective, the set of NISE is enriched in hydrolases, particularly carbohydrate hydrolases, and in enzymes involved in defense against oxidative stress.ConclusionsThese results indicate that at least some of the non-homologous isofunctional enzymes were recruited relatively recently from enzyme families that are active against related substrates and are sufficiently flexible to accommodate changes in substrate specificity.ReviewersThis article was reviewed by Andrei Osterman, Keith F. Tipton (nominated by Martijn Huynen) and Igor B. Zhulin. For the full reviews, go to the Reviewers' comments section.

Assembly of Lipoic Acid on Its Cognate Enzymes: an Extraordinary and Essential Biosynthetic Pathway

“…Note that, like LipB (75), LipM isolated from cells is acylated only with octanoate (the octanoyl-enzyme intermediate), indicating that octanoyl-ACP is the sole in vivo substrate (87). The LipM and LipB octanoyltransferases can be added to the list of enzymes that have undergone convergent evolution functionally and mechanistically (88,89). As previously stated, these enzymes are in the same family and have remarkably similar protein folding patterns (Fig.…”

“…Therefore, it appears that octanoyltransferase activity has evolved from the same protein scaffold through two different paths. This highlights the multitude of possible evolutionary outcomes and explains the rarity of true convergent evolution at the sequence level (88,89). …”

Evolution and Multiplicity of Arginine Decarboxylases in Polyamine Biosynthesis and Essential Role in Bacillus subtilis Biofilm Formation

“…There are thus four protein folds and eight different enzyme forms represented by the description EC 4.1.1.19. This is a rather extreme form of what have been recently described as, "non-homologous isofunctional enzymes" (8), enzymes carrying out the same chemistry but from entirely different evolutionary origins. The multiplicity of ADC forms indicates the importance of arginine decarboxylation and polyamine biosynthesis for life because different enzymatic solutions for arginine decarboxylation have arisen independently multiple times during evolution.…”

Diversity and Versatility of the Thermotoga maritima Sugar Kinome

“…The extensive sugar utilization machinery that has evolved to keep up with this nutritional diversity is characterized by a matching level of species-to-species variations. Among them are alternative biochemical routes, nonorthologous gene replacements, and variations of substrate specificity within large and divergent protein families (28). Therefore, although many components of the microbial sugar utilization machinery can be seamlessly recognized at the level of general class function (e.g., a putative sugar kinase of the FGGY family and a sugar transporter of the MFS family), an accurate assignment of their substrate specificity remains a challenging task.…”