Thiol cytosolic

Several additional points should be made. First, although oxygen esters usually have lower group-transfer potentials than thiol esters, the O—acyl bonds in acylcarnitines have high group-transfer potentials, and the transesterification reactions mediated by the acyl transferases have equilibrium constants close to 1. Second, note that eukaryotic cells maintain separate pools of CoA in the mitochondria and in the cytosol. The cytosolic pool is utilized principally in fatty acid biosynthesis (Chapter 25), and the mitochondrial pool is important in the oxidation of fatty acids and pyruvate, as well as some amino acids. 

This enzyme [EC 3.4.13.3] (also referred to as Xaa-His dipeptidase, X-His dipeptidase, aminoacylhistidine dipeptidase, and homocarnosinase), is a zinc-dependent dipeptidase that catalyzes the hydrolysis of Xaa-His dipeptides. Carnosine, homocarnosine, and anserine are preferred substrates for this mammalian cytosolic enzyme. Other aminoacylhistidine dipeptides are weaker substrates (including homoanserine). The enzyme is activated by thiols and inhibited by metal-chelating agents. O. W. Griffith (1986) Ann. Rev. Biochem. 55, 855. 

This process is an early morphological change in cells often seen in isolated cells in vitro but also known to occur in vivo. The blebs, which appear before membrane permeability alters, are initially reversible. However, if the toxic insult is sufficiently severe and the cellular changes become irreversible, the blebs may rupture. If this occurs, vital cellular components may be lost and cell death follows. The occurrence of blebs may be due to damage to the cytoskeleton, which is attached to the plasma membrane as described above. The cause may be an increase in cytosolic Ca2+, interaction with cytoskeletal proteins, or modification of thiol groups (see below). 

Probably the most important protective mechanisms involve the tripeptide GSH (chap. 4, Fig. 59). This compound is found in most cells, and in liver cells, it occurs at a relatively high concentration, about 5 mM or more. There are three pools of GSH cytosolic, mitochondrial, and nuclear. GSH structure is unusual for a peptide in the glutamyl, and cysteine residues are not coupled via a peptide bond, hence the molecule is resistance to peptidase attack. It has a nucleophilic thiol group, and it can detoxify substances in one of three ways ... 

Dennehy MK, Richards KAM, Wernke GR, et al. Cytosolic and nuclear protein targets of thiol-reactive electrophiles. Chem Res Toxicol 2006 19 20-29. 

Buchet, J.P. and Lauwerys, R. (1988) Role of thiols in the in-vitro methylation of inorganic arsenic by rat liver cytosol. Biochemical Pharmacology, 37(16), 3149-53. 

This enzyme uses cysteine conjugates as substrates, releasing the thiol of the xenobiotic, pyruvic acid, and ammonia, with subsequent methylation giving rise to the methylthio derivative. The enzyme from the cytosolic fraction of rat liver is pyridoxal phosphate requiring protein of about 175,000 daltons. Cysteine conjugates of aromatic compounds are the best substrates, and it is necessary for the cysteine amino and carboxyl groups to be unsubstituted for enzyme activity. 

Lewis CT, Seyer JM, Carlson GM (1989) Cysteine 288 an essential hyperreactive thiol of cytosolic phosphoenolpyruvate carboxykinase (GTP). J Biol Chem 264 27-33... 

Type I iodothyronine deiodinase is defined as the enzyme which catalyses the (mono)deiodination of the inner or the outer ring of different iodothyronines and which is inhibited by jrM concentrations of PTU [5-8]. In rats and humans, such enzyme activities are present at high levels in liver, kidneys and interestingly also in thyroid, and at low levels in many other tissues [5-8]. The deiodinase is associated with the microsomal fractions of these tissues but is only active in the presence of a cytoplasmic cofactor [5-8], Also, in the absence of cytosol, deiodinase activity is stimulated by simple thiols such as dithiothreitol (DTT) but the physiological cofactor has not yet been identified with certainty. The effects of synthetic and natural thiols will be discussed in Section 2.5. 

Thiol methyltransferase has been detected in erythrocytes, lymphocytes, lungs, cecal, and colonic mucosae. The nature and number of thiol methyltransferases is not clear at the present time. A cytosolic enzyme and a microsomal enzyme have been reported, with the microsomal enzyme being dissociated from membrane relatively easily. The microsomal enzyme in rat liver has been purified to homogeneity. The enzyme is a 28,000-dalton monomer with an isoelectric point of 6.2. A wide variety of xenobiotic thiols are methylated, but cysteine and glutathione are not substrates. S-Methylation is an important component in the thiomethyl shunt. Thiomethyl conjugates are metabolized to the methylsulfoxides by oxidation (see Chapter 10) and reenter the mercapturic acid pathway as substrates for glutathione S-transferase. 

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