In vivo modification

Metabolites are generated by the body s own biochemical processes as a way to facilitate excretion of xenobiotics. The enzymes catalysing in vivo modification of drugs and druglike molecules have a fundamental significance for the pharmaceutical industry. This was once primarily the field of the pharmacologist, but interest in metabolic reactions... 

Recent advances in mass spectrometry (MS) technology have provided researchers with an unparalleled ability to identify the types and patterns of secondary biochemical modifications found on proteins in living cells. Matrix-assisted laser desorption/ionization-MS (MALDI-MS) analyses have shown, for example, that HMGA proteins in vivo are simultaneously subject to complex patterns of phosphorylation, acetylation and methylation and that, within the same cell type, different isoforms of these proteins can exhibit quite different modification patterns [33]. Furthermore, these in vivo modifications have been demonstrated to markedly alter the binding affinity of HMGA proteins for both DNA and chromatin substrates in vitro [33]. Nevertheless, due to their number and complexity, it has been difficult to determine the actual biological function(s) played by these biochemical modifications in living cells. 

Sites of In vivo Modification of Human HMGAl Proteins Identified... 

Van Gelder In the absence of accurate absorption spectrum data the argument is moot. We have no idea what a cryptochrome actually does in vivo, so matching spectra does not apply to a pigment where you don t know what the in situ spectrum is. Many in vivo modifications could alter the absorption spectrum,... 

Sulser F, Owens ML, Dingell JV. in vivo modification of biochemical effects of reserpine by desipramine in the hypothalamus of the rat. Pharmacoiogist 1967 9 213(abst). 

The proteins produced by recombinant DNA technology are frequently accompanied by structural variants resulting from expression errors, in vivo modifications, posttranslational errors, improper folding, aggregation, and chemical modifications that occur during purification. The presence of vari-... 

Decreased biotin affinity ([22,31] in vivo modification of gene [28] and in vitro modification of protein (e.g. nitro-streptavidin) [32])... 

Since these early observation on the in vivo modification of stress-70 proteins, there has been further work documenting phosphorylation of several members of the stress-70 family, both in vitro and in vivo, and further exploration of the labeling of BiP by [ Hjadenosine in vivo. However, it is not yet clear what the significance of posttranslational modification of stress-70 proteins may be for regulating their activities. 

Rohrer DK, Kobilka BK. Insights from in vivo modification of adrenergic receptor gene expression. Annu Rev Pharmacol Toxicol 1998 38 351-373. 

Table III lists the most commonly encountered amino acid derivatives formed by in vivo modification of proteins during or after the completion of their ribosome-directed biosynthesis. In contrast to the strict alphabetical listing of Table II, the entries of this table have been organized in groups relative to the parent amino acid. It should be noted that this list is not exhaustive. There are several reports of covalent prosthetic group attachment to proteins through the side chains of a variety of residues (see Glazer et a/., 1975). In addition, carbohydrate is often found attached to proteins (Kornfeld and Kornfeld, 1976 Waechter and Lennarz, 1976) and there are reports of covalently bound lipid as well (Braun and Bosch, 1972 Stoffyn and Folch-Pi, 1971). However, for the most part, these amino acids have not been isolated as defined entities. A brief description of amino acid derivatives formed in vivo and their origin is given below.

Kreimeyer A, Wielckens K, Adamietz P et al. DNA repair-associated ADPribosylation in vivo. Modification of histone HI difiers from that of the principal acceptor proteins. J Biol Chem 1984 259(2) 890-6. 

The device most often used in the in vivo modification of the substrate is by the addition of unusual analogs of L-amino acids to the tissue culture medium. At moderate analog concentrations, viral protein synthesis continues, but the products contain the altered residues. This probably alters configuration of the precursors. 

W Huth, C Worm-Breitgoff, U Moller, I Wunderlich. Evidence for an in vivo modification of mitochondrial proteins by coenzyme A. Biochim Biophys Acta 1077 1-10, 1991. 

Recently, we have isolated the urea derivative of glucose, V-carbamoyl-P-D-glucopyranosylamine (glucose ureide), from human urine. We hypothesise that carbonyls react with urea in vivo to form urea derivatives, including ureides, which are then excreted as urinary constituents. In this experiment, we have developed a systematic approach for detection of urinary carbonyls in order to verify the in vivo modification of carbonyls with urea. 

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