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Melatonin for Prevention and Treatment of Complications Associated with Chemotherapy and Radiotherapy: Implications for Cancer Stem Cell Differentiation
Published in Paloma Tejero, Hernán Pinto, Aesthetic Treatments for the Oncology Patient, 2020
Germaine Escames, Ana Guerra-Librero, Dario Acuña-Castroviejo, Javier Florido, Laura Martinez-Ruiz, Cesar Rodríguez-Santana, Beatriz I Fernandez-Gil, Iryna Russanova
The synthesis of melatonin begins with the hydroxylation of tryptophan to 5-hydroxy-tryptophan (5HTP) by tryptophan-5-hydroxylase (TPOH). This product is subsequently decarboxylated to 5-hydroxy-L-tryptamine (serotonin or 5-HT) under the catalytic action of aromatic amino acid decarboxylase (AADC). Serotonin is then acetylated to N-acetylserotonin by arylalkylamine N-acetyltransferase (AANAT). Finally, N-acetylserotonin is methylated to melatonin by hydroxyindole-O-methyl transferase (HIOMT), now known as N-acetyl-serotonin methyltransferase (ASMT) [43], which is a melatonin synthesis rate-limiting enzyme inhibited by light [44]. Therefore, melatonin concentrations in serum, mainly originating from the pineal gland, follow a circadian pattern.
Biogenic amines
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
Disorders that lead to neurotransmitter imbalance include aromatic L-amino acid decarboxylase (AADC) deficiency, which also leads to both catecholamine and serotonin deficiency, tyrosine hydroxylase (TH) deficiency, and the dopamine transporter deficiency syndrome, which cause catecholamine deficiency. The disorders of BH4 synthesis (Chapter 16) also lead to abnormalities with the biogenic amine neurotransmitters.
Sympathetic Neurotransmission
Published in Kenneth J. Broadley, Autonomic Pharmacology, 2017
The next step in the synthesis of noradrenaline is decarboxylation of dopa to dopamine. This occurs in the cytoplasm of the neurone by the action of dopadecarboxylase (Figure 2.4). This enzyme is a relatively non-specific aromatic L-amino acid decarboxylase (EC 4.1.12.5) which also removes the carboxyl group from m-tyrosine, p-tyrosine, phenylalanine, methyldopa, the 5-hydroxytryptamine (serotonin) precursor, 5-hydroxytryptophan, and the histamine precursor, histidine. It has a Km for conversion of dopa to dopamine of 4 × 10–4 M. In common with tyrosine hydroxylase, it decarboxylates L-amino acids only, thus it is laevodopa that is administered for the treatment of Parkinson’s disease to raise central dopamine levels.
Burden and severity of disease of aromatic L-amino acid decarboxylase deficiency: a systematic literature review
Published in Current Medical Research and Opinion, 2022
Katharina Buesch, Rongrong Zhang, Katarzyna Szczepańska, Vladica Veličković, Lucy Turner, Milena Despotović, Branka Đorđević, Alexis Russell
Aromatic L-amino acid decarboxylase deficiency (AADCd) is an extremely rare and severe autosomal recessive disorder. Prevalence is uncertain and current predictions suggest birth rates of 1:90,000 in the US, 1:118,000 in Europe, and 1:182,000 in Japan1. The prevalence in the US population at risk is approximately 0.112% or 1:900, and the estimated new-born incidence in an at-risk population is approximately 1:41,000 to 1:68,000 births2. AADCd is caused by mutations in the dopa decarboxylase (DDC) gene that encodes the enzyme aromatic L-amino acid decarboxylase (AADC). AADC is a critical enzyme for the synthesis of the neurotransmitters dopamine and serotonin, which are essential mediators in the synthesis of melatonin, epinephrine, and norepinephrine3. An insufficient or complete lack of synthesis of these neurotransmitters leads to a phenotypic spectrum. In the majority of cases, signs and symptoms present during the first months of life resulting in severe motor and cognitive impairments that do not improve over time4. AADCd is a life-threatening condition for individuals without direct and dedicated caregiver support. For individuals with access to dedicated caregiver support, the management of AADCd requires consistent and lifelong care5. In routine clinical management, only symptomatic treatment is available, and response to treatment varies substantially among patients5. Novel gene therapies, using viral vectors containing the human DDC gene to substitute the defected gene, are emerging6,7.
Burden of illness of aromatic L-amino acid decarboxylase deficiency: a survey of physicians in Southern Europe
Published in Current Medical Research and Opinion, 2022
Samira Saberian, Philippa Rowan, Florence Hammes, Priya Patel, Fernando Fernandez-Cortes, Katharina Buesch, Igor Beitia Ortiz de Zarate
Aromatic L-amino acid decarboxylase deficiency (AADCd) is an ultra-rare genetic neurometabolic disorder caused by mutations in the DDC gene that results in a series of long-term morbidities1. It presents in infancy or early childhood. The incidence of AADCd has been estimated to range between 1:42,000 and 90,000 in the US2,3, 1:118,000 in Europe and 1:182,000 in Japan3. To date, 81 patients with AADCd have been described in the international JAKE database of pediatric neurotransmitter disorders (http://www.biopku.org/jake/jake_start.asp). The JAKE database collects clinical, biochemical and molecular data of patients with AADCd. In addition, 117–237 patient cases have been described in the literature4,5. Although the prevalence of AADCd in Europe is currently not accurately known, 27 cases from Europe were included in a recent international cohort of 63 patients6. However, newborn screening using a high-throughput method measuring 3-O-methyldopa in dried blood spots has recently become available and will allow for a more precise evaluation of the incidence of AADCd7.
Comparative examination of levodopa pharmacokinetics during simultaneous administration with lactoferrin in healthy subjects and the relationship between lipids and COMT inhibitory activity in vitro
Published in Nutritional Neuroscience, 2022
Masahiro Nagai, Madoka Kubo, Rina Ando, Masayuki Ikeda, Hiroshi Iwamoto, Yasuhiro Takeda, Masahiro Nomoto
PD is a neurodegenerative disorder that is characterized by the degeneration and death of dopaminergic neurons of the substantia nigra in the midbrain. Insufficient dopamine in the brain leads to the development of neurological symptoms, such as bradykinesia, muscle rigidity, and tremors. The gold standard PD therapy is the oral administration of the dopamine precursor levodopa. After absorption within the duodenum, levodopa passes through the blood–brain barrier and reaches the central nervous system. Levodopa is metabolized into dopamine by the aromatic L-amino acid decarboxylase in the striatum. The absorption of levodopa in the digestive tract is unstable, and its half-life is short (approximately 1 h). Therefore, levodopa concentrations in the blood easily fluctuate, and long-term use causes a diurnal variation of symptoms known as the wearing-off phenomenon [8]. As a countermeasure, levodopa or COMT inhibitors are frequently administered [9].