Comparison of Protein Acetyltransferase Action of CRTAase with the Prototypes of HAT

Abstract

Our laboratory is credited for the discovery of enzymatic acetylation of protein, a phenomenon unknown till we identified an enzyme termed acetoxy drug: protein transacetylase (TAase), catalyzing the transfer of acetyl group from polyphenolic acetates to receptor proteins (RP). Later, TAase was identified as calreticulin (CR), an endoplasmic reticulum luminal protein. CR was termed calreticulin transacetylase (CRTAase). Our persistent study revealed that CR like other families of histone acetyltransferases (HATs) such as p300, Rtt109, PCAF, and ESA1, undergoes autoacetylation. The autoacetylated CR was characterized as a stable intermediate in CRTAase catalyzed protein acetylation, and similar was the case with ESA1. The autoacetylation of CR like that of HATs was found to enhance protein-protein interaction. CR like HAT-1, CBP, and p300 mediated the acylation of RP utilizing acetyl CoA and propionyl CoA as the substrates. The similarities between CRTAase and HATs in mediating protein acylation are highlighted in this review.

Radiosensitization of calreticulin‐overexpressing human glioma cell line by the polyphenolic acetate 7, 8‐diacetoxy‐4‐methylcoumarin

“…33 Interestingly, the polyphenolic acetate DAMC that has been shown as a preferred acetyl group donor for the CRT-mediated protein acetylation sensitized the CRT-overexpressing cells (CROE) to a higher degree than the parental cells, suggesting its potential as an adjuvant to radiotherapy, particularly in CRT-linked radioresistant tumors. 27 Present study demonstrates that CRT overexpression changes intracellular physiology and enhances tumorigenic potential, revealed by 3D spheroid-like formation and increased growth rate in xenografts of tumors in nude mice (Figure 2). This augmentation in cellular function can be partially attributed to CRT-mediated rewiring of network of cell-to-cell interaction and communication, metabolic homeostasis, and protein stability (Ca 2+ , glucose uptake, and grp78).…”

“…However, our observation is at variance with the results reported earlier in U251 glioma cells where CRT overexpression resulted in radiosensitization, suggesting that the effect of CRT on radiation response could be cell‐type dependent and needs further investigations 33 . Interestingly, the polyphenolic acetate DAMC that has been shown as a preferred acetyl group donor for the CRT‐mediated protein acetylation sensitized the CRT‐overexpressing cells (CROE) to a higher degree than the parental cells, suggesting its potential as an adjuvant to radiotherapy, particularly in CRT‐linked radioresistant tumors 27 …”

“… 33 Interestingly, the polyphenolic acetate DAMC that has been shown as a preferred acetyl group donor for the CRT‐mediated protein acetylation sensitized the CRT‐overexpressing cells (CROE) to a higher degree than the parental cells, suggesting its potential as an adjuvant to radiotherapy, particularly in CRT‐linked radioresistant tumors. 27 …”

“…Our earlier investigations have established the transacetylase function of CRT wherein it efficiently transfers acetyl group from polyphenolic acetates (PAs) to target proteins while acetyl co-enzyme was a weak donor. [25][26][27] In vitro studies have established that among a variety of acetylated polyphenols with a varying number of acetyl group side chains, 7, 8-diacetoxy-4-methyl coumarin (DAMC) is an efficient acetyl group donor, acetylating the target proteins (enzymes) like cyto-P-450, NADPH-cyto c reductase, glutathione S transferase, and nitric oxide synthase modulating their activities and associated physiological effects. 28 Acetoxy drug: CRT transacetylase (CRTase) F I G U R E 1 Human glioma and head and neck cancers express a higher level of calreticulin gene compared to normal tissues.…”