COMT deficiency

In addition to the aforementioned inborn errors of metabolism, deficiencies in the catabolism of dopamine and serotonin would also be expected to result in decreased concentrations of HVA and 5HIAA (e.g. MAO deficiency and COMT deficiency). 

Some misinterpretations of the NBO performances still occur in the literature. For instance, 5-hydroxyguaiacyl (5-OH-G) units have been tentatively searched for among the NBO products recovered from transgenic tobacco plants deficient in caffeic acid 0-methyltransferase (COMT) activity [31], Studies on COMT-deficient bm3 maize line [32] have shown that the labile 5-OH-G units cannot survive NBO. This situation was anticipated in the pioneering studies of Kuc and Nelson [33], in which they suspected the occurrence of additional as yet undetected lignin units . By contrast and as explained in the next section, thioacidolysis provides an easy determination of 5-OH-G units in native or industrial lignins. 

Recently, a COMT-deficient Arabidopxis mutant was identified using the Versailles )S-glucuronidase promoter trap T-DNA collection by screening for GUS staining in root vascular tissues. The sinapoylmalate content of the AtOMTI mutant was approximately 50% that of wild type, and in its place, the mutant accumulates low levels of 5-hydroxyferuloylmalate and 5-hydroxyferuloylglucose, neither of which are observed in the wild type. 

After reuptake into the cytosol, some noradrenaline may be taken up into the storage vesicles by the vesicular transporter and stored in the vesicles for subsequent release (see above). However, it is thought that the majority is broken down within the cytosol of the nerve terminal by monoamine oxidase (MAO ECl.4.3.4). A second degradative enzyme, catechol-O-methyl transferase (COMT EC2.1.1.6), is found mostly in nonneuronal tissues, such as smooth muscle, endothelial cells or glia. The metabolic pathway for noradrenaline follows a complex sequence of alternatives because the metabolic product of each of these enzymes can act as a substrate for the other (Fig 8.8). This could enable one of these enzymes to compensate for a deficiency in the other to some extent. 

The number of drugs susceptible to S-methylation is still limited but greater than the number turned over by COMT. Thiopurine methyl transferase (TPMT) is an important enzyme responsible for detoxifying mercaptopurine—a drug used to treat leukemia— as well as azathioprine —a prodrug that is metabolized to mercaptopurine (Fig. 7.12). This enzyme is polymorphic and patients who are homozygous for the deficient enzyme experience severe toxicity when given usual doses of mercaptopurine (19). Similar aromatic and heterocyclic sulfhydryls can also be substrates for TPMT. The similar thiol... 

These findings suggest that dopamine deficiencies arising from MB-COMT promoter hypomethylation (i.e., increased expression) may influence promoter methylation and expression of RELN, DRD2, DRDl, and potentially other genes via coordinated epigenetic events that may aggravate disease symptoms (see Fig. 9.1). 

Carbidopa inhibits peripheral decarboxylation of levodopa, making more levodopa available for transport to the brain. Levodopa is a precursor of dopamine, which is deficient in parkinsonism patients. Entacapone inhibits the enzyme that metabohzes levodopa (catechol-O-methyltransferase [COMT]), which increases and prolongs levodopa plasma levels. The combination is indicated in the treatment of idiopathic Parkinson disease (1) to substitute (with equivalent strength of each of the 3 immediate-release components) for the previously administered individual products, (2) to replace immediate-release carbidopa/levodopa therapy (without entacapone) when patients experience signs and symptoms of end-of-dose wearing-off (only for patients taking a total daily dose of levodopa of 600 mg or less and not experiencing dyskinesias). 

Animal experiments [105] suggest that methylation of administered L-dopa to 3-methyldopa may lead to deficiency of the methyldonor methionine. As this is also required [40, 41] for the extraneuronal COMT pathway of DA metabolism it has been pointed out [195] that the synaptic effect of DA could be enhanced by the methionine deficiency. 

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