Enzyme Ephedrine

In a monograph on ephedrine Gaddum has reviewed the differences in the action of adrenaline and ephedrine and has suggested that the latter has the same relation to adrenaline as physostigmine has to acetylcholine, that is, ephedrine inhibits the action of an enzyme system, which normally destroys adrenaline, or the substance closely resembling it, produced by adrenergic nerves. 

Enzyme-substrate complex, 1041 Ephedrine, structure of, 65 Epibatidine, molecular model of. 332 Epichlorohydrin, epoxy resins from, 673-674 Epimer, 303... 

Interactions with caffeine and aspirin can increase the effects of ephedrine. Norepinephrine works in part by increasing the levels of cyclic aminomethyl propanol (AMP) in cells. Caffeine inhibits the enzyme that breaks down cyclic AMP. Together, ephedrine makes more cyclic AMP, and caffeine prevents it from breaking down. Aspirin inhibits the receptors that turn off release of norepinephrine. 

The main problems with early, irreversible MAOIs were adverse interactions with other drugs (notably sympathomimetics, such as ephedrine, phenylpropanolamine and tricyclic antidepressants) and the infamous "cheese reaction". The cheese reaction is a consequence of accumulation of the dietary and trace amine, tyramine, in noradrenergic neurons when MAO is inhibited. Tyramine, which is found in cheese and certain other foods (particularly fermented food products and dried meats), is normally metabolised by MAO in the gut wall and liver and so little ever reaches the systemic circulation. MAOIs, by inactivating this enzymic shield, enable tyramine to reach the bloodstream and eventually to be taken up by the monoamine transporters on serotonergic and noradrenergic neurons. Fike amphetamine, tyramine reduces the pH gradient across the vesicle membrane which, in turn, causes the vesicular transporter to fail. Transmitter that leaks out of the vesicles into the neuronal cytosol cannot be metabolised because... 

This enzyme [EC 2.S.2.2], also referred to as hydroxyste-roid sulfotransferase, catalyzes the reaction of 3 -phos-phoadenylylsulfate with an alcohol to produce adenosine 3, 5 -bisphosphate and an alkyl sulfate. The alcohols that can act as substrates include ahphatic alcohols, ascorbate, chloramphenicol, ephedrine, hydroxysteroids, and other primary and secondary alcohols. However, phenolic steroids will not serve as substrates (such alcohols can be acted upon by steroid sulfotransferases). 

Originally almost all apphcations of biocatalysis involved hydrolytic reactions, except a few, such as L-sorbose and ephedrine manufacture (Turner, 1994). Hydrolases still are the main conunercial enzyme class, but nowadays a much wider range of reactions is being applied, either on a conunercial scale or on a lab scale. The most important reaction types are reviewed in chapter 2. 

Pig liver esterase (PLE, E.C. 3.1.1.1) is one of the most successful enzymes for the enantiotopos-differentiating hydrolysis of dicarboxylic diesters and diacetates of diols as exemplified by the two examples, dimethyl cv. y-4-cydohexene-l,2-dicaiboxylate (I)100 - " 2 and (l/ ,2.S,3S)-l,3-di-acetoxy-2-nitrocyclohexane (3)113. The monoester 2 is obtained with the same results when prepared on a 100 mol scale114. The ee values of the monoester 2 may be determined conveniently by H-NMR spectroscopy in the presence of (+)- or ( )-ephedrine and that of the monoacetate 4, after conversion to the corresponding Mosher ester, by 19F-NMR spectroscopy. 

The reaction was already being used in the 1930s by Knoll (Ludwigshafen, Germany) (later BASF, since 2001 Abbott) (German Patent DE 546459, 1932) to produce ephedrine via (R)-phenylacetylcarbinol, (R)-PAC. Recently, efforts have been renewed to obtain an isolated enzyme process or a whole-cell process based on recombinant DNA technology. It was found that pyruvate could be substituted by the less expensive acetaldehyde, which did not produce C02 as a side product. 

Optimization of a continuous enzymic reaction yielding (R)-phenylacetylcarbinol (PAC), an L-ephedrine intermediate (Chapter 7, Section 7.5.2), from acetaldehyde and benzaldehyde with PDC from Zymomonas mobilis demonstrated that... 

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