Thyroidal biosynthesis of iodothyronines

Fischer, Allan G.; Schulz, Arthur R.; Oliner, Leo

doi:10.1016/0005-2744(68)90130-7

Cited by 46 publications

(7 citation statements)

References 20 publications

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“…The K , values, but not the molecular platelet MAO-B from individual to individual is due turnover numbers are dependent upon the pH of also to a variation in the concentration of otherwise the buffer medium in a manner consistent with the identical enzyme active centres (Oreland 1980; hypothesis that the unionized form of the substrate Fowler et al 1980a;, in line is the form preferentially metabolized by the enzyme with a similar finding for the variation in activity of (McEwen et al 1968;Williams 1974). In addition, rat brain MAO-A with age, estimated with a both molecular turnover numbers and K , values are [3H]harmaline binding assay (Nelson et al 1979a).increased with increasing oxygen concentration, Thus, it would seem that, under the right condisince M A 0 follows a ping-pong reaction pathway tions, the use of the acetylenic inhibitors to titrate the (Tipton 1968;Fischer et al 1968;Oi et al 1970; concentrations of MAO-A and -B can provide a Houslay & Tipton 1973; Roth 1979; Fowler & simple, but effective insight into the molecular Oreland 1980a). Thus, for given pH and oxygen changes taking place when the activity of M A 0 is concentrations, the K,, and maximum molecular influenced by either physiological, pathological or turnover numbers reflect the basic kinetic parabiochemical factors.…”

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confidence: 60%

“…increased with increasing oxygen concentration, Thus, it would seem that, under the right condisince M A 0 follows a ping-pong reaction pathway tions, the use of the acetylenic inhibitors to titrate the (Tipton 1968;Fischer et al 1968;Oi et al 1970; concentrations of MAO-A and -B can provide a Houslay & Tipton 1973;Roth 1979;Fowler & simple, but effective insight into the molecular Oreland 1980a). Thus, for given pH and oxygen changes taking place when the activity of M A 0 is concentrations, the K,, and maximum molecular influenced by either physiological, pathological or turnover numbers reflect the basic kinetic parabiochemical factors.…”

Section: Mechanism Of Inhibition Of Monoamine Oxidase and Its Applicamentioning

confidence: 99%

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The acetylenic monoamine oxidase inhibitors clorgyline, deprenyl, pargyline and J-508: their properties and applications

Fowler

Oreland

Callingham

1981

Journal of Pharmacy and Pharmacology

101

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The article presents a short review of some of the properties of the acetylenic inhibitors of monoamine oxidase currently under investigation: clorgyline, (-)-deprenyl, pargyline and 5-508. Their substrate-selective inactivation, mechanism of inhibition, titration and pharmacology with respect to monoamine oxidase are critically discussed.In 1968, Johnston showed that the irreversible acetylenic inhibitor clorgyline (N-methyl-N-propargyl-3-(2,4-dich1orophenoxy)-propylamine) inhibited the oxidative deamination of 5-hydroxytryptamine by rat brain monoamine oxidase (MAO, monoamine 0,: oxidoreductase (flavine containing), EC 1.4.3.4) at concentrations that were much lower than were required for the inhibition of benzylamine oxidation (Johnston 1968). When tyramine was used as substrate, a biphasic pattern of inhibition was found. Such a result has been found for a number of tissues, including the rat liver (Hall et al 1969, see Fig. I). Johnston (1968) suggested that these results were due to the presence of two forms of monoamine oxidase, which are now generally termed MAO-A and -B, where the -A form is sensitive to inhibition by clorgyline, and the -B form more resistant to inhibition. This conclusion was reinforced by the introduction of the MAO-B selective inhibitor (-)-deprenyl (phenyl-isopropy I-methyl-propinylamine) (Knoll & Magyar 1972) and its more potent analogue 5-508 (N-methyl-N-propargyl-(I-indany1)-ammonium hydrochloride) (Knoll et a1 1978). The structures of the compounds are given in Fig. 2. In addition, a variety of agents, ranging from the tricyclic noradrenaline uptake inhibitors to local anaesthetics, have been found to inhibit M A 0 activity in a substrate-selective manner (for review, see Fowler et a1 1978).In this article, the most commonly used substrateselective inhibitors, the acetylenic inhibitors of which clorgyline and (-)-deprenyl are the most well known, have been reviewed with respect to their properties, since it has been these compounds that have provided the main impetus for research in MA0 over the last decade. Substrate-specificity of monoamine oxidaseMost of the early studies with clorgyline and (-)-deprenyl were performed on either rat brain or liver, where it was shown that 5-hydroxytryptamine was the preferred substrate for MAO-A and benzylamine the preferred substrate for MAO-B, whilst tyramine was found to be deaminated by both enzyme forms (Johnston 1968; Hall et a1 1969). However, this substrate specificity is by no means universal. In Table I, the data published over the last ten years have been investigated in order to determine the frequency of occurrence of the metabolism of a given substrate by a given enzyme form. The 'common substrate' tyramine, for example, is in fact metabolized by both enzyme forms in only 29 out of 51 tissues (see Table I). Most of the possible combinations of the substrate specificities of the two forms of M A 0 have been reported. Some examples of 'unusual' combinations towards three of the most commonly used substrates are shown in Table 2...

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confidence: 60%

Section: Mechanism Of Inhibition Of Monoamine Oxidase and Its Applicamentioning

confidence: 99%

The acetylenic monoamine oxidase inhibitors clorgyline, deprenyl, pargyline and J-508: their properties and applications

Fowler

Oreland

Callingham

1981

Journal of Pharmacy and Pharmacology

101

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“…It would thus seem likely that rat liver mitochondrial monoamine oxidase, being a flavoprotein (Sourkes, 1968), proceeds in a similar fashion to the Initochondrial monoamine oxidases of pig brain (Tipton, 1968b), ox liver (Oi et al, 1970) and bovine thyroid (Fischer et al, 1968) where the free modified form of the enzyme is that with its flavin reduced.…”

Section: Kinetic Investigationmentioning

confidence: 99%

“…Monoamine oxidase preparations from ox thyroid (Fischer et al, 1968), pig brain (Tipton, 1968b) and ox liver (Oi et al, 1970) have been shown to obey a double-displacement kinetic mechanism when acting on amine substrates, although the oxidation of hydrazones by pig brain monoamine oxidase has been shown to obey a kinetic mechanism that does not involve the fornation of a free modified form of the enzyme (Tipton & Spires, 1971).…”

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The reaction pathway of membrane-bound rat liver mitochondrial monoamine oxidase

Houslay

Tipton

1973

Biochemical Journal

110

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1. A preparation of a partly purified mitochondrial outer-membrane fraction suitable for kinetic investigations of monoamine oxidase is described. 2. An apparatus suitable for varying the O(2) concentration in a spectrophotometer cuvette is described. 3. The reaction catalysed by the membrane-bound enzyme is shown to proceed by a double-displacement (Ping Pong) mechanism, and a formal mechanism is proposed. 4. KCN, NaN(3), benzyl cyanide and 4-cyanophenol are shown to be reversible inhibitors of the enzyme. 5. The non-linear reciprocal plot obtained with impure preparations of benzylamine, which is typical of high substrate inhibition, is shown to be due to aldehyde contamination of the substrate.

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