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Parkinson’s Disease and Aging: Presynaptic Nigrostriatal Function
Published in W. R. Wayne Martin, Functional Imaging in Movement Disorders, 2019
The enzymatic processes involved in the formation and metabolism of dopamine have been well characterized. Tyrosine hydroxylase is the initial and rate-limiting enzyme in the biosynthetic pathway.12 This enzyme catalyzes the hydroxylation of tyrosine to form 3,4-dihydroxy-l-phenylalanine (l-DOPA, or levodopa) and is located in dopamine-synthesizing neurons. Levodopa is then decarboxylated to dopamine by aromatic l-amino acid decarboxylase (ALAAD) which is present in highest concentration in the brain within striatal dopaminergic nerve endings.13 The conversion of tyrosine to levodopa, and levodopa to dopamine occurs within the cytosol and is immediately followed by the uptake of dopamine into storage vesicles in the nerve terminals. When an action potential reaches the nerve terminal, stored dopamine is released into the synaptic cleft. The action of dopamine released in this fashion is terminated primarily by a specific, energy-requiring reuptake process into the presynaptic terminal.14 In addition, two enzymes are responsible for the catabolism of dopamine. Monoamine oxidase (MAO) is located on the outer layer of mitochondria15 and plays an important role in the inactivation of free dopamine within the nerve terminal. Catechol O-methyl transferase (COMT) is located on the outer plasma membrane of cells,16 thus acting on extraneuronal dopamine. The major metabolic products of dopamine are dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA).
Velo-cario-Facial Syndrome
Published in Merlin G. Butler, F. John Meaney, Genetics of Developmental Disabilities, 2019
Wendy R. Kates, Kevin Antshel, Wanda Fremont, Nancy Roizen, Robert J. Shprintzen
A number of studies have proposed candidate genes within the deleted region in relation to specific anomalies or groups of anomalies (29–32). At this time, it seems likely that at least two genes can be linked to some of the VCFS phenotype. Because the 22q11.2 genome is well preserved across species, its homolog has been isolated to mouse chromosome 16. Using animal models, investigators have determined that haploin-sufficiency of the gene TBX1 results in the same conotruncal heart anomalies commonly found inVCFS (31). The gene COMT (catechol-O-methyltransferase) has been linked to psychiatric disorders in relation to the metabolism and degradation of synaptic dopamine levels (30,33). COMT is responsible for the degradation of dopamines and therefore has been hypothesized to have an effect on neural transmission. COMT has been found to have a polymorphism, two alleles that have different activity levels with regard to their ability to degrade dopamines: a low secreting heat labile version, and a high secreting stable version (30). Hemizygosity for the low secreting version has been linked to a higher frequency of psychiatric disorders in individuals with VCFS (30). Both of these genes reside within the commonly deleted region for VCFS and all individuals who are FISH positive for the deletion will be missing single copies of TBX1 and COMT.
Choice Impulsivity
Published in Hanna Pickard, Serge H. Ahmed, The Routledge Handbook of Philosophy and Science of Addiction, 2019
Annabelle M. Belcher, Carl W. Lejuez, F. Gerard Moeller, Nora D. Volkow, Sergi Ferré
Several genes have been identified as possible moderators of CI. The two most prominent are the gene for catechol-O-methyltransferase (COMT) and the dopamine D4 receptor (D4R) gene, inferred from the association of specific gene polymorphisms with differences in the degree of DD. COMT is a main dopamine-degrading enzyme in the prefrontal cortex. Different gene polymorphic variants lead to differential levels of COMT activity (Lachman et al. 1996; Chen et al. 2004). Low COMT activity (also demonstrated pharmacologically with the COMT inhibitor tolcapone) leads to an increased DD (Kayser et al. 2012). More specifically, there is compelling evidence for a U-shaped relationship between CI and COMT activity, as shown from experiments on genotype x drug (tolcapone) and genotype x age interaction experiments. Depending on the genotype and age, COMT inhibition can increase or decrease DD (Smith and Boettiger 2012; Farrell et al. 2012).
The neurochemistry of hypnotic suggestion
Published in American Journal of Clinical Hypnosis, 2021
David J. Acunzo, David A. Oakley, Devin B. Terhune
A final line of evidence bearing on a role for dopamine in hypnosis comes from studies of the genetic polymorphisms underlying hypnotic suggestibility. A candidate gene is that coding for Catechol-O-methyl transferase (COMT), which is directly involved in prefrontal dopamine degradation, and whose Val158Met (rs4680) genetic variants degrade dopamine at different speeds (Lachman et al., 1996). Previous research suggests a link between this polymorphism and executive functions (Bilder, Volavka, Lachman, & Grace, 2004), and placebo responding (Colloca et al., 2019). Studies of the link between this polymorphism and suggestibility have yielded conflicting results. Two studies (Lichtenberg, Bachner-Melman, Ebstein, & Crawford, 2004; Lichtenberg, Bachner-Melman, Gritsenko, & Ebstein, 2000) found effects differing according to gender. Raz, Fossella, McGuiness, Zephrani, and Posner (2004) reported that val/met participants were the most highly suggestible whereas Szekely et al. (2010) reported an additive suggestibility effect of the val allele (see also Katonai et al., 2017). However, two studies (Rominger et al., 2014; Storozheva et al., 2018) observed that it was the met/met genotype that was characterized by the highest suggestibility. Finally, other studies failed to observe or report any links (Bryant, Hung, Dobson-Stone et al., 2013; Presciuttini et al., 2014; see also U. Ott, Reuter, Hennig, & Vaitl, 2005). Taken together, these results are equivocal and indicate that potential links between the COMT polymorphism and suggestibility are at best complex.
Inhibition of catechol-O-methyltransferase by natural pentacyclic triterpenes: structure–activity relationships and kinetic mechanism
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Fang-Yuan Wang, Gui-Lin Wei, Yu-Fan Fan, Dong-Fang Zhao, Ping Wang, Li-Wei Zou, Ling Yang
Catechol-O-methyltransferase (COMT, C.E. 2.1.6) is a bisubstrate enzyme, that catalyses methyl transfer from S-adenosyl-L-methionine (SAM) to one of the hydroxyls of catecholamine neurotransmitters dopamine, epinephrine and norepinephrine, and catechol oestrogens, resulting in termination of their biological activity1,2. The catalytic site consisted of SAM and catechol binding pockets connected by a narrow channel through which methyl transfer occurs, where the SAM site proved to be deeply embedded1. COMT followed an ordered reaction mechanism where SAM bound first to the enzyme and the catechol substrate followed by release of the products in the reverse order3. COMT is a therapeutic target for the treatment of various peripheral cancers4–6 and central system disorders7–10. In particular, inhibition of peripheral COMT offers a unique advantage, since COMT inhibitors are clinically used as adjunct to levodopa (L-dopa) for the treatment of Parkinson’s disease7.
Cheminformatics and virtual screening studies of COMT inhibitors as potential Parkinson’s disease therapeutics
Published in Expert Opinion on Drug Discovery, 2020
Kalliopi Moschovou, Georgia Melagraki, Thomas Mavromoustakos, Lefteris C. Zacharia, Antreas Afantitis
COMT inhibitors are of paramount importance in Parkinson’s disease for symptom alleviation when used in combination with L-DOPA aiming at increasing L-DOPA’s bioavailability. Many attempts have been made to develop COMT inhibitors but only three are currently marketed with significant side effects and limitations. Hepatotoxicity has been the major concern which resulted in market withdrawing of some inhibitors. Two others common COMT inhibitors’ side effects are diarrhea, which is non-related to dopaminergic effects, and dyskinesia which is related to dopaminergic effects. On the other hand, an important challenge in PD treatment is to minimize the OFF time (which is the time that the treatment is losing its efficacy), and increase ON time, a property related to the efficacy and the pharmacokinetic properties of the drug. In the absence of any disease modifying treatments, the above challenges need to be met, and in silico methods provide an important tool to effectively address these issues.