The evolution of function within the Nudix homology clan

Abstract

The Nudix homology clan encompasses over 80,000 protein domains from all three domains of life, defined by homology to each other. Proteins with a domain from this clan fall into four general functional classes: pyrophosphohydrolases, isopentenyl diphosphate isomerases (IDIs), adenine/guanine mismatch-specific adenine glycosylases (A/G-specific adenine glycosylases), and non-enzymatic activities such as protein/protein interaction and transcriptional regulation. The largest group, pyrophosphohydrolases, encompasses more than 100 distinct hydrolase specificities. To understand the evolution of this vast number of activities, we assembled and analyzed experimental and structural data for 205 Nudix proteins collected from the literature. We corrected erroneous functions or provided more appropriate descriptions for 53 annotations described in the Gene Ontology Annotation database in this family, and propose 275 new experimentally-based annotations. We manually constructed a structure-guided sequence alignment of 78 Nudix proteins. Using the structural alignment as a seed, we then made an alignment of 347 “select” Nudix homology domains, curated from structurally determined, functionally characterized, or phylogenetically important Nudix domains. Based on our review of Nudix pyrophosphohydrolase structures and specificities, we further analyzed a loop region downstream of the Nudix hydrolase motif previously shown to contact the substrate molecule and possess known functional motifs. This loop region provides a potential structural basis for the functional radiation and evolution of substrate specificity within the hydrolase family. Finally, phylogenetic analyses of the 347 select protein domains and of the complete Nudix homology clan revealed general monophyly with regard to function and a few instances of probable homoplasy.

Volatile Compounds Are Involved in Cellular Crosstalk and Upregulation

“…For example, both setups of monoculture and same cell unconnected co-culture show an increase in cell-metabolism related compounds, such as 3-methyl-3-buten-1-ol (The Human Metabolome Database, HMDB, registry HMDB0030126), that can have both endogenous and exogenous source and relate to cell signaling. This compound may be part of the byproducts of dolichols in the mevalonate pathway, [27] or byproducts of isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP) that can also be hydrolyzed by different Nudix hydrolase enzymes, [28] like isopentenyl-diphosphate delta-isomerase 1 (HMDBP01541). Another interesting finding is the increase of 3-methyl-butanal (aka iso-valeraldehyde) in all same cells unconnected co-culture pairs (Table S11, Supporting Information).…”

The Prodigal Compound: Return of Ribosyl 1,5-Bisphosphate as an Important Player in Metabolism

“…The Nudix box has the consensus sequence GX 5 EX 7 REUXEEXGU (where U represents leucine, isoleucine, or valine and X may be any amino acid) and forms part of the catalytic site for diphosphate hydrolysis (82). The three-dimensional structures of numerous Nudix hydrolases have been determined (83), including the C. elegans Ap 4 A hydrolase ( Fig. 5A) (60).…”

The complex enzymology of mRNA decapping: Enzymes of four classes cleave pyrophosphate bonds

“…Nudix hydrolases are the principal members of the large nudix superfamily, “nudix” standing for “nucleoside diphosphate linked to a variable moiety X” (Bessman, Frick, & O'Handley, ). The superfamily contains diverse proteins, most having pyrophosphohydrolase activity or nucleotide‐binding properties (McLennan, , ; Srouji, Xu, Park, Kirsch, & Brenner, ). All nudix proteins possess a variant of the four‐stranded beta‐grasp domain architecture comprising roughly 130 amino acids (Burroughs, Balaji, Iyer, & Aravind, ).…”