Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:6.2.1.1 (ACS)
 78,556 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Reduced dopamine neurotransmission in the prefrontal cortex has been implicated as causal for the negative symptoms and cognitive deficit associated with schizophrenia; thus, a compound which selectively enhances dopamine neurotransmission in the prefrontal cortex may have therapeutic potential. Inhibition of catechol-O-methyltransferase (COMT, EC 2.1.1.6) offers a unique advantage, since this enzyme is the primary mechanism for the elimination of dopamine in cortical areas. Since membrane bound COMT (MB-COMT) is the predominant isoform in human brain, a high throughput screen (HTS) to identify novel MB-COMT specific inhibitors was completed. Subsequent optimization led to the identification of novel, non-nitrocatechol COMT inhibitors, some of which interact specifically with MB-COMT. Compounds were characterized for in vitro efficacy versus human and rat MB and soluble (S)-COMT. Select compounds were administered to male Wistar rats, and ex vivo COMT activity, compound levels in plasma and cerebrospinal fluid (CSF), and CSF dopamine metabolite levels were determined as measures of preclinical efficacy. Finally, novel non-nitrocatechol COMT inhibitors displayed less potent uncoupling of the mitochondrial membrane potential (MMP) compared to tolcapone as well as nonhepatotoxic entacapone, thus mitigating the risk of hepatotoxicity.
ACS Chem Neurosci 2012 Feb 15
PMID:Characterization of non-nitrocatechol pan and isoform specific catechol-O-methyltransferase inhibitors and substrates. 2286 Jan 82

For decades, there has been debate regarding the origin of the catalytic power of enzymes. In this work, we use the approach of computational chemistry to study the enzyme catechol O-methyltransferase (COMT) and reveal that the two current views on the catalytic mechanism of enzymes, the rate-promoting vibrations and the electric field, may both be viewed as part of the chemical step catalyzed by COMT. However, we show that the rate-promoting vibrations cause the electrostatic effect. This work provides insight into the catalytic mechanism of COMT and resolves a longstanding controversy regarding this enzyme's mechanism.
ACS Catal 2019 Nov 01
PMID:Examining the Origin of Catalytic Power of Catechol O-Methyltransferase. 3175 9