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Liver alcohol dehydrogenase kinetics

Von Wartburg JP, Bethune JL, Vallee BL. Human liver alcohol dehydrogenase. Kinetic and physicochemical properties. Biochemistry 1964 3 1775-1782. [Pg.241]

In the following year, Cleland and his coworkers reported further and more emphatic examples of the phenomenon of exaltation of the a-secondary isotope effects in enzymic hydride-transfer reactions. The cases shown in Table 1 for their studies of yeast alcohol dehydrogenase and horse-liver alcohol dehydrogenase would have been expected on traditional grounds to show kinetic isotope effects between 1.00 and 1.13 but in fact values of 1.38 and 1.50 were found. Even more impressively, the oxidation of formate by NAD was expected to exhibit an isotope effect between 1.00 and 1/1.13 = 0.89 - an inverse isotope effect because NAD" was being converted to NADH. The observed value was 1.22, normal rather than inverse. Again the model of coupled motion, with a citation to Kurz and Frieden, was invoked to interpret the findings. [Pg.41]

Isotope effects have also been applied extensively to studies of NAD+/NADP+-linked dehydrogenases. We typically treat these enzymes as systems whose catalytic rates are limited by product release. Nonetheless, Palm clearly demonstrated a primary tritium kinetic isotope effect on lactate dehydrogenase catalysis, a finding that indicated that the hydride transfer step is rate-contributing. Plapp s laboratory later demonstrated that liver alcohol dehydrogenase has an intrinsic /ch//cd isotope effect of 5.2 with ethanol and an intrinsic /ch//cd isotope effect of 3-6-4.3 with benzyl alcohol. Moreover, Klin-man reported the following intrinsic isotope effects in the reduction of p-substituted benzaldehydes by yeast alcohol dehydrogenase kn/ko for p-Br-benzaldehyde = 3.5 kulki) for p-Cl-benzaldehyde = 3.3 kulk for p-H-benzaldehyde = 3.0 kulk for p-CHs-benzaldehyde = 5.4 and kn/ko for p-CHsO-benzaldehyde = 3.4. [Pg.406]

Horse liver alcohol dehydrogenase (HLADH (E.C. 1.1.1.1), commercially available) is a well-documented enzyme capable of catalyzing the enantioselective oxidation of acyclic and cyclic meso-configurated dimethanol derivatives to chiral lactols and further to the corresponding chiral lactones with high enantioselectivity and in high yield (Table 11) 162 ,69. Incases where the two enantiomeric lactols are formed, a kinetic enantiomer separation can occur in the second oxidation step166. [Pg.636]

For example, liver alcohol dehydrogenase was crystallized as the enzyme N AD1 p-bromobenzyl alcohol complex with saturating concentrations of substrates in an equilibrium mixture51b and studied at low resolution. Transient kinetic studies or direct spectroscopic determinations led to the conclusion that the internal equilibrium (E NAD alcohol = E NADH aldehyde) favors the NAD1 alcohol complex.52 Subsequently, the complex was studied at higher resolution, and the basic structural features were confirmed with a... [Pg.773]

Based on these results, attempts have been made to apply enantioselective dehydrogenations with horse liver alcohol dehydrogenase HLADH, E.C. 1.1.1.1), in the presence of NAD+, for kinetic resolution of the isomeric (hydroxyalkyl)silanes rac-105, rac- 107... [Pg.2395]

H. THEORELtand B. Chance, Liver alcohol dehydrogenase. II. Kinetics of the compound of horse-liver alcohol dehydrogenase and reduced diphosphopyridine nudeotide, Acta Chem. Scand. 1951, 5, 1127-1144. [Pg.280]

Burnell JC, Bosron WF. Genetic polymorphism of human liver alcohol dehydrogenase and kinetic properties of the isoenzymes. In Crow KE, Batt RD, eds. Human Metabolism of Alcohol. Vol. 2. Boca Raton, Florida CRC Press, Inc., 1989 65-75. [Pg.242]

The steady-state kinetic studies of liver alcohol dehydrogenase (12.5 nM) are performed. The initial rates (v in /rM/rnin) with varying substrate concentrations in both directions (forward for ethanol oxidation and reverse for ethanal reduction) are given below. Evaluate their kinetic parameters and equilibrium constant. [Pg.142]

Studies on the various zinc-activated dehydrogenases continue apace. The reduction of tra s-4-iViV-dimethylaminocinnamaldehyde (A) by liver alcohol dehydrogenase (LADH) is reported to involve the zinc at the active site of the enzyme acting as a Lewis acid and co-ordinating the substrate via the aldehyde oxygen.235 The kinetics of the reaction show that (A) 4- LADH -f NADH form a stable intermediate at pH 9, the overall reaction sequence being ... [Pg.463]

Experimental data on primary and secondary kinetic isotope effects in the hydride-transfer step in liver alcohol dehydrogenase, LADH, were analyzed using canonical variational transition theory (CVT) for overbarrier dynamics and the optimized multidimentional path (OMT) for the nuclear tunneling (Alhambra et al., 2000 and references therein). This work demonstrates somewhat better agreement of theoretical values of primary and secondary Schaad- Swein exponents calculated by combining CVT/OMT methods with the experimental values instead of CVT and classical transition states (TST). [Pg.60]

In addition to stereoselective metalation, other methods have been applied for the synthesis of enantiomerically pure planar chiral compounds. Many racemic planar chiral amines and acids can be resolved by both classical and chromatographic techniques (see Sect. 4.3.1.1 for references on resolution procedures). Some enzymes have the remarkable ability to differentiate planar chiral compounds. For example, horse liver alcohol dehydrogenase (HLADH) catalyzes the oxidation of achiral ferrocene-1,2-dimethanol by NAD to (S)-2-hydroxymethyl-ferrocenealdehyde with 86% ee (Fig. 4-2la) and the reduction of ferrocene-1,2-dialdehyde by NADH to (I )-2-hydroxymethyl-ferrocenealdehyde with 94% ee (Fig. 4-2lb) [14]. Fermenting baker s yeast also reduces ferrocene-1,2-dialdehyde to (I )-2-hydroxymethyl-ferro-cenealdehyde [17]. HLADH has been used for a kinetic resolution of 2-methyl-ferrocenemethanol, giving 64% ee in the product, (S)-2-methyl-ferrocenealdehyde... [Pg.197]

The molecular details of the action of metalloenzymes have begun to be elucidated in the past few years (42). Crystal structures for bovine carboxypeptidase A (43), thermolysin (44), and horse liver alcohol dehydrogenase (45) are now available, and chemical and kinetic studies have defined the role of zinc in substrate binding and catalysis. In fact, many of the significant features elucidating the mode of action of enzymes in general have been defined at the hands of zinc metalloenzymes. [Pg.123]

Billeter, S.R., et al. (2001). Hydride transfer in liver alcohol dehydrogenase quantum dynamics, kinetic isotope effects, and role of enzyme motion. J. Am. Chem. Soc. 123, 11262-11272... [Pg.301]

Pocker Y, Li H. 1990. Kinetics and mechanism of methanol and formaldehyde interconversion and formaldehyde oxidation catalyzed by liver alcohol dehydrogenase. Adv Exp Med Biol 284 315-325. [Pg.420]

Now it is worth making enantiomerically enriched 90. One method already in the literature14 involved reduction of racemic 90 with horse liver alcohol dehydrogenase. This is an enzymatic kinetic resolution (chapters 28 and 29) and at 50% reduction the products are 31% unreacted ketone 90 in good ee, 33% of one enantiomer of the anti-alcohol 93 in perfect (100%) ee, and a trace of the vvn-alcohol 93. [Pg.730]

Recently, a controversial debate has arisen about whether the optimization of enzyme catalysis may entail the evolutionary implementation of chemical strategies that increase the probability of tunneling and thereby accelerate reaction rates [7]. Kinetic isotope effect experiments have indicated that hydrogen tunneling plays an important role in many proton and hydride transfer reactions in enzymes [8, 9]. Enzyme catalysis of horse liver alcohol dehydrogenase may be understood by a model of vibrationally enhanced proton transfer tunneling [10]. Furthermore, the double proton transfer reaction in DNA base pairs has been studied in detail and even been hypothesized as a possible source of spontaneous mutation [11-13]. [Pg.34]

Agarwal, P. K., Iordanov, T., Hammes-Schiffer, S., Hydride Transfer in Liver Alcohol Dehydrogenase Quantum Dynamics, Kinetic Isotope Effects, and Role of Enzyme Motion, J. Am Chem. Soc. 2001, 123, 11262-11272. [Pg.1202]

LADHee and that the activity disappeared after carboxymethylation of a cysteine residue at the active site of LADH s [145]. In a recent study by Okuda and Okuda it was demonstrated that the -hydroxysteroid dehydrogenase activity in human liver was associated with a major isoenzyme of liver alcohol dehydrogenase (/82, 2) that the activity was inhibited by a chelating agent for Zn, which resides in the active site of the enzyme [146], Kinetic studies with the highly purified isoenzyme showed that neither a Theorell-Chance mechanism nor a simple ordered BiBi mechanism applied to the reaction. Evidence was obtained that the reaction was asymmetric in both directions. It has been established by Fukuba that the 4A-hydro-gen in NADH is involved [147]. [Pg.252]

Alhambra C, Corchado J, Sanchez M, Garcia-Viloca M, Gao J, Truhlar DG. Canonical variational theory for enzyme kinetics with the protein mean force and multidimensional quantum mechanical tunneling dynamics. Theory and application to liver alcohol dehydrogenase. J Phys Chem B 2001 105 11326-11340. [Pg.812]

Fig. 14. Based on the insensitivity toward substituent effects, the transition state for horse liver alcohol dehydrogenase is expected to be reactant-like, and with little charge buildup on the hydrogen to be transferred. The electron distribution in the nicotinamide ring is not known. The ring could retain pyridinium character, with only modest positive charge density at C-4, as shown in (a). Alternatively the charge could even reside entirely at C-4, as shown in (b) following rehybridization at N-1. Secondary N kinetic isotope effects have been reported to support the latter picture (60) however, further studies have failed to corroborate these results (61) (W. W. Cleland, personal communication), leaving the question open. Fig. 14. Based on the insensitivity toward substituent effects, the transition state for horse liver alcohol dehydrogenase is expected to be reactant-like, and with little charge buildup on the hydrogen to be transferred. The electron distribution in the nicotinamide ring is not known. The ring could retain pyridinium character, with only modest positive charge density at C-4, as shown in (a). Alternatively the charge could even reside entirely at C-4, as shown in (b) following rehybridization at N-1. Secondary N kinetic isotope effects have been reported to support the latter picture (60) however, further studies have failed to corroborate these results (61) (W. W. Cleland, personal communication), leaving the question open.

See other pages where Liver alcohol dehydrogenase kinetics is mentioned: [Pg.170]    [Pg.61]    [Pg.660]    [Pg.1012]    [Pg.198]    [Pg.40]    [Pg.60]    [Pg.63]    [Pg.1361]    [Pg.37]    [Pg.94]    [Pg.328]    [Pg.280]    [Pg.143]    [Pg.7]    [Pg.20]    [Pg.24]    [Pg.25]    [Pg.30]    [Pg.31]    [Pg.39]    [Pg.44]    [Pg.47]   
See also in sourсe #XX -- [ Pg.94 ]




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