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  • In mammals COMT is present

    2020-08-05

    In mammals, COMT is present in two molecular forms: a soluble cytoplasmic form (S-COMT) and a membrane protein (MB-COMT) with similar kinetic mechanism. The main difference is the lower Michaelis constant (K) value for MB-COMT for catecholamines and higher maximum reaction rate (V) for S-COMT from human NP118809 australia and from cells containing recombinant S- or MB-COMT . This makes S-COMT the predominant isoform of the enzyme, especially at high concentrations of substrate (i.e., during pregnancy). However, the mechanisms linking human COMT to PE remain unclear. It is not entirely known, for example, why both lower concentrations and lower activity of COMT have been noted in human preeclamptic placentas. A possible explanation involves a common polymorphism in the gene encoding for COMT in exon 5 (substitution of valine [Val] for methionine [Met] at codon 108 for the S-COMT and at 158 for the MB-COMT; rs4680) , resulting in reduced thermostability and activity of the enzyme . An association between the functional Val158Met polymorphism and PE has been reported, but most of the studies derived only from maternal genotyping. However, it is clear that the placenta plays a key role in the pathogenesis of this disease, because its expulsion terminates the syndrome. Therefore, the fetal genes may be of critical importance influencing the mother\'s susceptibility to PE, but at the present little is known about placental COMT genotypes and PE. Additionally, previous data further suggest that COMT activity is more precisely determined by three haplotypes of four SNPs inherited together, rs6269, rs4633, rs4818, and rs4680, which may result in a 25-fold difference in enzyme activity . In this regard, Hill et al. reported the association of the low-activity COMT haplotype with an increased risk for preeclampsia in Chilean maternal-fetal dyads population. Elevated homocysteine has been considered to be a risk factor for vascular dysfunction, vascular disease, and preeclampsia , . The methionine-homocysteine metabolism is responsible for supplying COMT with the methyl-group donor (-adenosyl methionine; SAM) necessary for 2-ME synthesis, and alterations in this pathway may be related to inability to sustain adequate concentrations of 2-ME during pregnancy, leading to the classic clinical picture of PE . Low levels of SAM may be caused by the presence of single-nucleotide polymorphisms (SNPs) in the genes that code for the enzymes involved in SAM metabolism. Methylenetetrahydrofolate reductase (MTHFR) modulates the availability of SAM, and the minor T allele of the MTHFR C677T SNP has been associated with reduced MTHFR activity, resulting in a decrease in SAM production . This may be important, because the low-activity COMT and MTHFR genotypes are frequently associated in cases of PE .
    Introduction Cognitive impairment is one of the most common and devastating nonmotor symptoms of Parkinson\'s disease (PD). Cognitive deficit is present in 24%–62% of patients with newly diagnosed PD, and dementia occurs in more than 80% of patients within two decades of disease onset [[1], [2], [3]]. These data suggest that only 15% of patients with PD may remain cognitively intact in the long-term disease course [3]. Therefore, identifying the factors that determine cognitive decline and determining how they relate to subsequent dementia are crucial.