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Asparagine peptide lyases: a seventh catalytic type of proteolytic enzymes.

ABSTRACT: The terms "proteolytic enzyme" and "peptidase" have been treated as synonymous, and all proteolytic enzymes have been considered to be hydrolases (EC 3.4). However, the recent discovery of proteins that cleave themselves at asparagine residues indicates that not all peptide bond cleavage occurs by hydrolysis. These self-cleaving proteins include the Tsh protein precursor of Escherichia coli, in which the large C-terminal propeptide acts as an autotransporter; certain viral coat proteins; and proteins containing inteins. Proteolysis is the action of an amidine lyase (EC 4.3.2). These proteolytic enzymes are also the first in which the nucleophile is an asparagine, defining the seventh proteolytic catalytic type and the first to be discovered since 2004. We have assembled ten families based on sequence similarity in which cleavage is thought to be catalyzed by an asparagine.

SUBMITTER: Rawlings ND

PROVIDER: S-EPMC3207474 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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Asparagine peptide lyases: a seventh catalytic type of proteolytic enzymes.

Rawlings Neil David ND Barrett Alan John AJ Bateman Alex A

The Journal of biological chemistry 20110808 44

The terms "proteolytic enzyme" and "peptidase" have been treated as synonymous, and all proteolytic enzymes have been considered to be hydrolases (EC 3.4). However, the recent discovery of proteins that cleave themselves at asparagine residues indicates that not all peptide bond cleavage occurs by hydrolysis. These self-cleaving proteins include the Tsh protein precursor of Escherichia coli, in which the large C-terminal propeptide acts as an autotransporter; certain viral coat proteins; and pro ...[more]

PMID: 21832066

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Project description:We report the results of an investigation into the catalytic role of highly conserved amide (asparagine, glutamine) and OH-containing (serine, tyrosine) residues in several prenyltransferases. We first obtained the X-ray structure of cyclolavandulyl diphosphate synthase containing two molecules of the substrate analog dimethylallyl (S)-thiolodiphosphate (DMASPP). The two molecules have similar diphosphate group orientations to those seen in other ζ-fold (cis- head-to-tail and head-to-middle) prenyltransferases with one diphosphate moiety forming a bidentate chelate with Mg2+ in the so-called S1 site (which is typically the allylic binding site in ζ-fold proteins) while the second diphosphate binds to Mg2+ in the so-called S2 site (which is typically the homoallylic binding site in ζ-fold proteins) via a single P1O1 oxygen. The latter interaction can facilitate direct phosphate-mediated proton abstraction via P1O2, or more likely by an indirect mechanism in which P1O2 stabilizes a basic asparagine species that removes H+, which is then eliminated via an Asn-Ser shuttle. The universal occurrence of Asn-Ser pairs in ζ-fold proteins leads to the idea that the highly conserved amide (Asn, Gln) and OH-containing (Tyr) residues seen in many "head-to-head" prenyltransferases such as squalene and dehydrosqualene synthase might play similar roles, in H+ elimination. Structural, bioinformatics and mutagenesis investigations indeed indicate an important role of these residues in catalysis, with the results of density functional theory calculations showing that Asn bound to Mg2+ can act as a general (imine-like) base, while Gln, Tyr and H2O form a proton channel that is adjacent to the conventional (Asp-rich) "active site". Taken together, our results lead to mechanisms of proton-elimination from carbocations in numerous prenyltransferases in which neutral species (Asn, Gln, Ser, Tyr, H2O) act as proton shuttles, complementing the more familiar roles of acidic groups (in Asp and Glu) that bind to Mg2+, and basic groups (primarily Arg) that bind to diphosphates, in isoprenoid biosynthesis.

Dataset Information

Asparagine peptide lyases: a seventh catalytic type of proteolytic enzymes.

Publications

Asparagine peptide lyases: a seventh catalytic type of proteolytic enzymes.

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