Liver tertiary structure

It was originally assumed that in LADH the zinc existed in an octahedral form with six bonds available for coordination, until in 1967 Vallee and co-workers showed that the enzyme contained two different types of zinc atom.13773 Loss of two zinc atoms from the enzyme resulted in loss of catalytic activity but maintained the tertiary structure. It was postulated from this that one metal ion per subunit played a role maintaining the tertiary structure, while the other zinc functioned in a catalytic role. Only two of the zinc ions in the liver enzyme interact with the inhibitors 1,10-phenanthroline and 2,2 -bipyridyl, thus demonstrating the different chemical reactivities of the zinc ions.1378 It was also shown that one zinc per subunit could be selectively exchanged or removed by dialysis. This modified enzyme containing one zinc per subunit did not bind 1,10-phenanthroline, hence the catalytic zinc is removed first during dialysis.1379 The second zinc atom can be selectively removed in preference to the catalytic zinc, by carboxymethylation followed by dialysis.1377 ... 

The hydride transfer step is a direct transfer between substrate and coenzyme. The suggestion by Schellenberg (363,369) that tryptophan mediates this hydride transfer in the yeast enzyme has been shown chemically not to be valid for both yeast and liver enzyme (93,370-373). Furthermore, the tertiary structure shows that the two tryptophans of the LADH subunit are both approximately 20 A away from the active site... 

Preliminary X-ray diffraction data for crystalline chicken liver GDH and Neurospora NADP-GDH are characteristic of unit cells too complex for straightforward determination of tertiary structure. 

Peptides and proteins are metabolized quite extensively in the kidney, liver, and gastrointestinal (Gl) tract via the enzymatic hydrolysis of the peptide bond. Metabolism also can occur in nasal mucosa, the lung, and blood. Because large proteins can assume complex tertiary structures, which thus better shields, or hides, internal peptide bonds, they often are metabolized more slowly, or less completely, than smaller proteins or polypeptides (20). 

Horse liver ADH is a very universal enzyme with a broad substrate specificity and excellent stereoselectivity. Historically, it is the most widely used dehydrogenase in biotransformations [775, 776]. The three-dimensional structure has been elucidated by X-ray diffraction [778]. Although the primary sequence is quite different, the tertiary structure of HLADH is similar to that of YADH [779]. The most useful applications of HLADH are found in the reduction of medium-ring monocyclic ketones (four- to nine-membered ring systems) and bicyclic ketones [780-782]. Sterically demanding molecules which are larger than decalines are not readily accepted and acyclic ketones are usually reduced with modest enantioselec-tivities [783, 784]. 

Dinuclaotida fold a characteristic folded protein structure constituting part or all of the structure of four NAD-dependent dehydrogenases, and certain other enzymes, some of which do not bind nucleotides. The D.f. was first identified in the tertiary structures of liver alcohol dehydrogenase (EC l.l.l.l), gly-... 

The breakdown of glycogen in skeletal muscles and the liver is regulated by variations in the ratio of the two forms of glycogen phosphorylase. The a and b forms differ in their secondary, tertiary, and quaternary structures the active site undergoes changes in structure and, consequently, changes in catalytic activity as the two forms are interconverted. 

The tertiary bile acids are formed in the liver as well as in the gut. (s. fig. 3.3) Intestinally absorbed lithocholic acid is enzymatically converted to sulpholitho-cholic acid in the liver. Ketolithocholic acid is transformed to (hypercholeretic) ursodeoxycholic acid in both the intestine and the liver. When passing through the canaliculi, UDC is partly reabsorbed by epithelial cells and returned to the liver via the blood circulation (= cholehepatic shunt). (41) The latter is chemically and structurally identical to chenodeoxycholic acid, of which it is deemed to be the 7P-epimer ... 

In rat liver ADH the presence of multiple molecular forms has been correlated to disulfide bridges involving the ligands to this zinc atom (Section II,B,3). These forms are active in ethanol oxidation (62). The lobe region which binds zinc is thus, in all probability, not essential for the catalytic action of alcohol oxidation. It has been suggested (133,134) that the extra zinc atom is essential for the structural stability of the enzyme. There is no evidence in the structure that this lobe region is necessary either for tertiary or quaternary structure stabilization. From the structural point of view, this region looks much more like a second catalytic center. The zinc atom is situated in one side of an obvious cleft into which the lone pair electrons of the sulfur atom of Cys-97 project. 

Phosphorylation of proteins probably occurs after translation of the protein (81). f-RNA specific for phosphoserine occurs in rat and rooster liver, but it has not been shown that the phosphorylated amino add can be incorporated directly into proteins (82). In this case, it appears that serine is phosphorylated after it combines with the specific f-RNA (83, 84). Sites of phosphorylation are probably determined by the amino acid sequence of die protein (see below), and extent of phosphorylation may be limited by formation of secondary, tertiary, and quaternary structure. 

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