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Human DOPA Decarboxylase: Catalysis and Involvement in Pharmacological Treatments for Parkinson’s Disease and Aromatic Amino Acid Decarboxylase Deficiency
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2020
Mariarita Bertoldi, Giada Rossignoli
Human L-3,4-dihydroxyphenylalanine (l-DOPA) decarboxylase (DDC, E.C. 4.1.1.28) is the enzyme responsible for the synthesis of the essential neurotransmitters dopamine and serotonin derived by decarboxylation from the corresponding amino acids l-DOPA and L-5-hydroxytryptophan (l-5HTP). The enzyme is more appropriately defined as aromatic amino acid decarboxylase (AADC) since it is able to accommodate in its active site aromatic rings of different sizes with a cathechol or an indole side chain. In addition, it can slowly convert other aromatic amino acids, such as p-tyrosine, tryptophan, and tyrosine, into the so-called aromatic trace amines whose role as neuromodulators is still partially unraveled. Hence, the enzyme represents a key point in controlling aromatic amines levels. DDC is present in the central nervous system, where it controls neurotransmitters synthesis, but also in the kidneys, in the liver and in suprarenal glands where it catalyzes a committed step in the reaction pathway leading to the synthesis of norepinephrine and epinephrine (Bertoldi, 2014).
Vitamins and Nutrition
Published in Richard J. Sundberg, The Chemical Century, 2017
In 1989, physicians in New Mexico noted and reported several cases of elevated white count with muscle pain (eosinophilia–myalgia syndrome) and associated it with use of the amino acid l-tryptophan as a dietary supplement. In November, the CDC issued a warning and advised consumers to discontinue use of l-tryptophan. By 1993, a total of about 1500 cases and 37 deaths had been reported to CDC. There were six producers of l-tryptophan at the time, all in Japan. Investigation showed that only lots from Showa Denka manufactured after 1988 were associated with the syndrome. Showa Denka manufactured the amino acid using a recombinant strain of Bacillus amyloliquefaciens and had modified their process just before the outbreak. They had also modified the purification process, reducing the amount of adsorbent charcoal used. Although the material was 99.6% pure, it contained numerous minor impurities, one of which was evidently the cause of the syndrome.35l-Tryptophan was removed from the market, despite the evidence that an impurity was the cause of the toxicity. It has been replaced by 5-hydroxytryptophan, a compound one step further down the metabolic chain in the production of the neurotransmitter serotonin.36
Irritable bowel syndrome and the gut microbiota
Published in Journal of the Royal Society of New Zealand, 2020
Phoebe E. Heenan, Jacqueline I. Keenan, Simone Bayer, Myrthe Simon, Richard B. Gearry
Abnormalities in the metabolism of gut hormones and neurotransmitters observed in IBS patients could be a common mechanism for both altered transit and visceral hypersensitivity. A significantly lower density of enteroendocrine cells (ECs) have been demonstrated in IBS patients (Gunawardene et al. 2011; El-Salhy 2012; El-Salhy and Gilja 2017). ECs produce and secrete GI hormones and neurotransmitters in response to the luminal environment as well as signals from the CNS, ANS and ENS (Mawe et al. 2006; Camilleri 2012; El-Salhy 2012; El-Salhy et al. 2012). ECs also mediate the communication between the ENS, ANS and CNS and are therefore involved in both the modulation of GI sensation and motility, this has been reviewed in detail elsewhere (Wade et al. 1996; May and Kaestner 2010; Gunawardene et al. 2011; El-Salhy 2012; El-Salhy et al. 2012; Gershon 2013). One of the predominant neurotransmitters produced by ECs is serotonin. Serotonin has a vital role in the regulation of colonic motility as well as secretion and sensation, and is a vital neurotransmitter within and between the CNS and the ENS (Sikander et al. 2009). Abnormal metabolism of serotonin and its precursor, 5-hydroxytryptophan, have been associated with IBS pathophysiology, as well as the different IBS subtypes, for a number of years (Pata et al. 2002; Dunlop et al. 2005). Interestingly a recent study conducted in Norway has found that modulating the gut microbiota of IBS patients through various different methods increased EC cell density towards the level of healthy controls, which was associated with improvements to symptoms and quality of life (Mazzawi et al. 2013, 2016).