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Catalytic Site Atlas

CSA LITERATURE entry for 1a4y

E.C. nameANGIOGENIN
SpeciesHomo sapiens (Human)
E.C. Number (IntEnz) 3.1.27.-
CSA Homologues of 1a4yThere are 263 Homologs
CSA Entries With UniProtID
CSA Entries With EC Number 3.1.27.-
PDBe Entry 1a4y
PDBSum Entry 1a4y
MACiE Entry 1a4y

Literature Report

IntroductionAngiogenin is a ribonuclease which induces neovascularisation. It binds specifically to endothelial cells in culture and elicits second-messenger responses. It also binds heparin and can serve as a substratum for endothelial cell adhesion. Its amino acid sequence is 33% identical to that of bovine pancreatic ribonuclease RNase A and it has the same general catalytic properties as RNase A, however, it differs markedly both in magnitude and in specificity with RNase A.
Angiogenin was first isolated from culture medium conditioned by adenocarcinoma cells, and has since been shown to be critical for the establishment and/or metastatic spread of a wide variety of human tumors in athymic mice, most likely by supporting the growth of tumor vasculature. Moreover, clinical studies have revealed increased Angiogenin expression to be associated with progression of several human cancers. These findings identify Angiogenin as a promising target for new anticancer drugs.
MechansimThe cleavage of substrate by ribonucleases is a two-step reaction: the first step is a transesterification of which a nucleophilic displacement at the phosphorus atom of the 5' leaving group by the 2' entering oxygen atom takes place, forming a nucleoside 2',3'-cyclophosphate intermediate, which is hydrolysed in the second step to yield the product.
His13 acts as a base to abstract a proton from 2'-oxygen of a substrate molecule, and thereby facilitates its attack on the phophorus atom. This attack proceeds inline to displace a nucleoside. His114 acts as an acid to protonate the 5''-oxygen to facilitate its displacement. The subsequent hydrolysis resembles the reverse of transphosphorylation where His114 activates a water molecule by deprotonation to facilitate its nucleophilic attack. Lys40 stabilises the transition state.

Catalytic Sites for 1a4y

Annotated By Reference To The Literature - Site 1 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
HisB1337macie:sideChainIt abstracts a proton from 2'-oxygen of a substrate molecule, and thereby facilitates its attack on the phosphorous atom and acts as a base in the subsequent hydrolysis.
LysB4064macie:sideChainIt stabilises the transition state.
HisB114138macie:sideChainIt acts as an acid to protonate the 5''-oxygen to facilitate its displacement of the leaving group. It activates a water nucleophile by deprotonation.

Annotated By Reference To The Literature - Site 2 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
HisE1337macie:sideChainIt abstracts a proton from 2'-oxygen of a substrate molecule, and thereby facilitates its attack on the phosphorous atom and acts as a base in the subsequent hydrolysis.
LysE4064macie:sideChainIt stabilises the transition state.
HisE114138macie:sideChainIt acts as an acid to protonate the 5''-oxygen to facilitate its displacement of the leaving group. It activates a water nucleophile by deprotonation.

Literature References

Notes:
Shapiro R
Site-directed mutagenesis of histidine-13 and histidine-114 of human angiogenin. Alanine derivatives inhibit angiogenin-induced angiogenesis.
Biochemistry 1989 28 7401-7408
PubMed: 2479414
Shapiro R
Role of lysines in human angiogenin: chemical modification and site-directed mutagenesis.
Biochemistry 1989 28 1726-1732
PubMed: 2497770
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