Reductases species differences

An interesting species difference might be pointed out. The above HMG-CoA reductase inhibitors inhibit HMG-CoA reductase from a variety of animals, and reduce serum cholesterol in humans, rabbits and dogs, but do not reduce serum chr lesterol in rats and mice (Sakono et ai, 1996). 

Why then, since such an abundance of metabolic inhibitors is available, do so few of them find practical application Examples are the folic acid reductase inhibitors, such as aminopterin, the purine and pyrimidine analogs used as cytostatics in cancer chemotherapy and known for their high toxicity in a wide variety of species, and the organic phosphates and carbamates used as insecticides but also highly toxic to mammals. Lack of selectivity in the action of metabolic inhibitors is inherent in their mechanism of action due to the universality of biochemical processes and principles throughout nature. Selectivity in action requires species differences in biochemistry. For the antivitamins, for instance, there is not only a lack of species differences in action in addition, the fact that vitamins often serve as cofactors for a variety of enzymes is a serious drawback to endeavors to obtain agents with species-selective action. 

Reviews.—The following have been reviewed species differences among i jwdrofolate reductases,Ho ethambutol laboratory and clinical studies,29>... 

Stolk JM, Smith RP. 1966. Species differences in methemoglobin reductase activity. Biochem Pharmacol 15 343-351. 

Liang T, Cascieri MA, Cheung AH, et al. Species differences in prostatic steroid 5a-reductases of rat, dog, and human. Endocrinology 1985 117 571-579. 

Species differences in the in v/tro metabolic reduction of acetohexamide were studied (54) In rabbit, guinea pig, hamster, rat and mouse. The rabbit exhibited the highest acetohexamide reductase activity in the cytosol of the liver and kidney among the species tested. The sensitivity to specific inhibitors of cytosolic acetohexamide reductase in the liver and kidney of the rabbit were different from those of the rat. Only rats and guinea pigs showed significant activity of acetohexamide reductase activity In the microsomes of the liver and kidney. 

Almost all of the Mo and W enzymes show paramagnetic pentavalent forms that can be studied by methods such as EPR spectroscopy, and EPR in particular has been extensively used to study the enzymes. Beeause the pentavalent form is typieally only a fraction of the total metal present, few parallel studies using XAS have been reported. Rhodobacter DMSO reduetase, however, is one notable exeeption. In this case there are two different forms that show essentially 100% of Mo as the Mo(v) form. The first is an inhibited species, which forms with vicinal diols such as glycerol, and is a stable Mo(v) entity that is resistant to both oxidation and reduction. This species was studied in the first XAS report on DMSO reductase, and was fou nd to be a six-coordinate complex with four equivalent sulfurs and two Mo-0 bonds, probably from the vicinal diol coordinated to Mo(v). The stability of this spe-eies means that it has little catalytic relevance, but the second quantitatively Mo(v) DMSO reductase species is formed by reduction with the alternative substrate trimethylamine Af-oxide (TMAO). This substrate forms the most... 

Species differences in methemoglobin reductase activity exist. 

Rundles and Brewer (1958) have shown that methionine aggrevates bone marrow megaloblastosis and its addition to bone marrow cultures from vitamin deficient patients does not alleviate defective DNA synthesis (Waxman, 1969 Metz, 1968). This antifolate" effect of methionine in bone marrow cultures is in contrast to the "pro-folate effect described in rat liver. A species difference s not involved because similar results were found in rat bone marrow cultures (Cheng et al., 1975) leading to the hypothesis that methionine exerts its primary effect as an end-product inhibitor of the homocysteinetransmethylase reaction rather than regulation (via SAM) of 5 10 methylene THF reductase. It is also possible that the tissue culture system used to study bone marrow metabolism does not reflect the normal cellular environment. As Krebs et al. (1976) have pointed out, isolated normal hepatocytes have lost low molecular weight constituents including methionine and are incapable of some reactions known to occur in vivo. 

The utilization of IR spectroscopy is very important in the characterization of pseudopolymorphic systems, especially hydrates. It has been used to study the pseudopolymorphic systems SQ-33600 [36], mefloquine hydrochloride [37], ranitidine HC1 [38], carbovir [39], and paroxetine hydrochloride [40]. In the case of SQ-33600 [36], humidity-dependent changes in the crystal properties of the disodium salt of this new HMG-CoA reductase inhibitor were characterized by a combination of physical analytical techniques. Three crystalline solid hydrates were identified, each having a definite stability over a range of humidity. Diffuse reflectance IR spectra were acquired on SQ-33600 material exposed to different relative humidity (RH) conditions. A sharp absorption band at 3640 cm-1 was indicative of the OH stretching mode associated with either strongly bound or crystalline water (Fig. 5A). The sharpness of the band is evidence of a bound species even at the lowest levels of moisture content. The bound nature of this water contained in low-moisture samples was confirmed by variable-temperature (VT) diffuse reflectance studies. As shown in Fig. 5B, the 3640 cm-1 peak progressively decreased in intensity upon thermal... 

Dihydroflavonol 4-reductase (DFR EC 1.1.1.219) is a member of the short-chain dehydrogenase/reductase family and catalyzes the stereospecific conversion of (+)-(2R,3R)-dihydroflavonols to the corresponding (2R,3S,4S) flavan-3,4-cw-diols (leucoanthocyanidins), with NADPH as a required cofactor. The enzyme activity was first identified in cell suspension cultures of Douglas fir (Pseudotsuga menziesii) and was shown to be related to the accumulation of flavan-3-ols and proanthocyanidins [96]. Leucoanthocyanidins and DFR were later shown to be required for anthocyanidin formation by complementation of Matthiola incana mutants blocked between dihydroflavonol and anthocyanidin biosynthesis [97, 98], DFR has been purified to apparent homogeneity and biochemically analyzed from flower buds of Dahlia variabilis [99]. DFR was shown to accept different substrates depending on the plant species from which it was isolated (reviewed in 100). 

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