Enzymatic activity of toxic and non‐toxic type 2 ribosome‐inactivating proteins

Abstract

Ribosome-inactivating proteins (RIPs) display adenine polynucleotide glycosylase activity on di¡erent nucleic acid substrates, which at the ribosomal level is responsible for the arrest of protein synthesis. Some type 2 RIPs, namely ricin and related proteins, are extremely toxic to mammalian cells and animals whilst other type 2 RIPs (non-toxic type 2 RIPs) display three to four logs less toxicity. We studied whether a correlation exists between toxicity on cells and enzymatic activity on nucleic acids. All type 2 RIPs di¡er in their depurinating activity on the di¡erent substrates with di¡erences of up to one to two logs. The toxicity of type 2 RIPs is independent of their enzymatic activity on nucleic acids or on ribosomes.

Ricinus communis Agglutinin I Leads to Rapid Down-Regulation of VEGFR-2 and Endothelial Cell Apoptosis in Tumor Blood Vessels

“…Inhibition of protein synthesis by RCA I A chain internalized into endothelial cells would also contribute to the reduction in VEGFR-2. 12,13 Down-regulation of VEGFR-2 after binding and internalization of RCA I was followed by loss of patency and cessation of blood flow. Some endothelial cells of tumor vessels underwent apoptosis, as documented by the appearance of activated caspase-3 staining that colocalized with CD31.…”

“…To determine whether the striking decrease of VEGFR-2 immunoreactivity of tumor vessels after injection of RCA I was due to a selective effect on VEGFR-2 or to a generalized action of RCA I on protein synthesis, 12,17,18 we asked whether similar changes occurred in other endothelial cell membrane proteins, VEGFR-3, CD31, and CD105.…”

“…9 -13 The sequence of the A and B chains of RCA I and ricin have homologies but are not identical. 12 The A chain of RCA I and ricin is cytotoxic because its glycosidase activity inactivates ribosomal protein synthesis; the B chain is a lectin that mediates endocytosis by binding galactosyl and N-acetylgalactosaminyl residues of cell surface glycoconjugates. syndrome found with immunotoxins or other therapeutics containing ricin A chain.…”

Riproximin’s activity depends on gene expression and sensitizes PDAC cells to TRAIL

“…1 These proteins consist of two chains, which exhibit complementary properties. 2 The A chain is an rRNA N-glycosidase, which causes depurination of the 28S rRNA in a catalytic manner and thus leads to transcriptional arrest by inhibiting protein synthesis. 3 The B-chain binds to glycan structures and is prerequisite for internalization of the RIP type II molecule.…”

“…16 Based on this background, new drugs are needed for the treatment of PDAC. We reasoned that it would be worth investigating 2 , and Martin R Berger the activity of Rpx in PDAC models, because a colorectal cancer liver metastasis model had shown explicit antineoplastic activity. 1 Moreover, the affinity of Rpx for carcinoembryonic antigen (CEA) 5 suggested that neoplasias expressing this glycoprotein might be preferential targets.…”