Glutathione catalysis and the reaction mechanisms of glutathione-dependent enzymes.

The glyoxalase system is present in the cytosol of cells and cellular organelles, particularly mitochondria. It is found throughout biological life and is thought to be ubiquitous. The widespread distribution and presence of the glyoxalase system in living organisms suggests it fulfils a function of fundamental importance to biological life. Recent investigations have brought new developments in the involvement of the glyoxalase in cell growth and vesicle mobilization, with increasing evidence of changes in the glyoxalase system during tumor growth and diabete mellitus, particularly relating to the development of associated clinical complications.

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The glyoxalase system: new developments towards functional characterization of a metabolic pathway fundamental to biological life.

Molecular characterization of the stretch-induced adaptation of cultured cardiac cells. An in vitro model of load-induced cardiac hypertrophy.

Aldehydes are organic compounds that are widespread in nature. They can be formed endogenously by lipid peroxidation (LPO), carbohydrate or metabolism ascorbate autoxidation, amine oxidases, cytochrome P-450s, or myeloperoxidase-catalyzed metabolic activation. This review compares the reactivity of many aldehydes towards biomolecules particularly macromolecules. Furthermore, it includes not only aldehydes of environmental or occupational concerns but also dietary aldehydes and aldehydes formed endogenously by intermediary metabolism. Drugs that are aldehydes or form reactive aldehyde metabolites that cause side-effect toxicity are also included. The effects of these aldehydes on biological function, their contribution to human diseases, and the role of nucleic acid and protein carbonylation/oxidation in mutagenicity and cytotoxicity mechanisms, respectively, as well as carbonyl signal transduction and gene expression, are reviewed. Aldehyde metabolic activation and detoxication by metabolizing enzymes are also reviewed, as well as the toxicological and anticancer therapeutic effects of metabolizing enzyme inhibitors. The human health risks from clinical and animal research studies are reviewed, including aldehydes as haptens in allergenic hypersensitivity diseases, respiratory allergies, and idiosyncratic drug toxicity; the potential carcinogenic risks of the carbonyl body burden; and the toxic effects of aldehydes in liver disease, embryo toxicity/teratogenicity, diabetes/hypertension, sclerosing peritonitis, cerebral ischemia/neurodegenerative diseases, and other aging-associated diseases.

Aldehyde sources, metabolism, molecular toxicity mechanisms, and possible effects on human health.

Due to the obvious advantages of long-acting peptide and protein drugs, strategies to prolong plasma half life time of such compounds are highly on demand. Short plasma half life times are commonly due to fast renal clearance as well as to enzymatic degradation occurring during systemic circulation. Modifications of the peptide/protein can lead to prolonged plasma half life times. By shortening the overall amino acid amount of somatostatin and replacing l-analogue amino acids with d-amino acids, plasma half life time of the derivate octreotide was 1.5 hours in comparison to only few minutes of somatostatin. A PEG2,40 K conjugate of INF-α-2b exhibited a 330-fold prolonged plasma half life time compared to the native protein. It was the aim of this review to provide an overview of possible strategies to prolong plasma half life time such as modification of N- and C-terminus or PEGylation as well as methods to evaluate the effectiveness of drug modifications. Furthermore, fundamental data about most important proteolytic enzymes of human blood, liver and kidney as well as their cleavage specificity and inhibitors for them are provided in order to predict enzymatic cleavage of peptide and protein drugs during systemic circulation.

Strategies to improve plasma half life time of peptide and protein drugs

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/0014-5793%2889%2981797-1

Martti Koivusalo

Papers

Evidence for the identity of glutathione-dependent formaldehyde dehydrogenase and class III alcohol dehydrogenase.

Formaldehyde Dehydrogenase from Human Liver PURIFICATION, PROPERTIES, AND EVIDENCE FOR THE FORMATION OF GLUTATHIONE THIOL ESTERS BY THE ENZYME

Different forms of rat liver aldehyde dehydrogenase and their subcellular distribution.

Significance of sterol structural specificity. Desmosterol cannot replace cholesterol in lipid rafts.

Liver aldehyde and alcohol dehydrogenase activities in rat strains genetically selected for their ethanol preference.