Molecular Aspects of the Activity and Inhibition of the FAD-Containing Monoamine Oxidases
Peter Grunwald in Pharmaceutical Biocatalysis, 2019
Covalent attachment (at the C8 position of FAD in MAO), bending, and the surrounding protein groups alter the redox potential in flavoproteins. The two-electron redox potential for FAD in solution is −0.23 V and is the similar for the cysteinyl-FAD in MAO (about −0.2 V). The redox potential for amine oxidation is greater than +1 V, so for amine to reduce MAO requires a large adjustment from binding to the protein. FADH2 readily reacts with oxygen producing hydrogen peroxide (H2O2) (+0.3 V). In amine oxidases, the reoxidation is thought to proceed via a C4a hydroperoxy intermediate (Mattevi, 2006). Although the catalytic reaction is a two-electron reduction, with hydride transfer the most likely mechanism, FAD is a versatile one or two electron acceptor. When MAO is reduced by dithionite in the presence of mediator dyes, inhibitors stabilize the anionic semiquinone form (Hynson et al., 2004).
Reactivities of Amino Acids and Proteins with Iodine
Erwin Regoeczi in Iodine-Labeled Plasma Proteins, 2019
Recent studies indicate that tyrosyl rings are involved in biological processes by stacking (i.e., alignment with other ring structures). Thus, oligopeptides containing tyrosine stack with nucleic acid bases as shown by proton magnetic resonance, fluorescence spectroscopy, and difference absorption spectroscopy.157 This interaction, only demonstrable with single-stranded structures, is not abolished by methylation of the phenoic OH group. Energy transfer from the tyrosine to the nucleic acid is inferred from fluorescence quenching. Tyrosine could therefore possibly play a role in the selective recognition of single strands by proteins. Similarly, tyrosyl residues of flavoproteins stack parallel with flavin, suggesting that the reduction of oxidized flavin may be facilitated by charge transfer.158
Multiple acyl CoA dehydrogenase deficiency/glutaric aciduria type II ethylmalonic-adipic aciduria
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop in Atlas of Inherited Metabolic Diseases, 2020
The fundamental molecular defect is in the mitochondrial transport of electrons from the acylCoAs to ubiquinone (CoQ10) of the main electron transport chain [5–7]. The transfer of electrons from the 2,3 positions of a number of important energy-providing substrates requires the concerted activities of the electron transfer flavoprotein (ETF), a mitochondrial matrix protein, and the electron transfer flavoprotein: Ubiquinone oxidoreductase (ETF-QO), which is an inner mitochondrial membrane protein that transfers electron to coenzyme Q in the respiratory chain. The defect may be in any of three proteins, the alpha or beta subunits of ETF or its dehydrogenase, ETF-QO (EC 1.5.5.1). Both are flavoproteins. Another designation has been IIA and IIB for defects in the α and β proteins and IIC for ETF-QO defects.
Privileged multi-target directed propargyl-tacrines combining cholinesterase and monoamine oxidase inhibition activities
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Zofia Chrienova, Eugenie Nepovimova, Rudolf Andrys, Rafael Dolezal, Jana Janockova, Lubica Muckova, Lenka Fabova, Ondrej Soukup, Patrik Oleksak, Martin Valis, Jan Korabecny, José Marco-Contelles, Kamil Kuca
Monoamine oxidases (EC 1.4.3.4) catalyse the oxidation of monoamines. These flavoproteins are bound to the outer mitochondrial membrane. In humans, there are two types of MAO: MAO-A and MAO-B. Both isoforms are abundantly present in neurons and glial cells. MAO-A is omnipresent in liver, gastrointestinal tract, or placenta, whereas MAO-B, apart from the central nervous system (CNS), is also produced by blood platelets9. The main biological role of MAO-A is the catabolism of neurotransmitters such as serotonin, epinephrine, norepinephrine, and dopamine. The activity of this enzyme increases only slightly with age10. On the other hand, MAO-B is responsible for the decomposition of phenylethylamine, benzylamine, and dopamine11. The most significant increase in MAO-B concentration is caused by the proliferation of glial cells10. Such phenomenon may thus contribute to an excessive reduction of MAO levels in the brain in the elderly. Moreover, it has been confirmed that the activity of MAO increases with the progression of AD. Within the process of amines oxidation, MAO produces aldehydes, ammonia, and hydrogen peroxide. It is particularly hydrogen peroxide that evokes the development of neuronal oxidative stress by disrupting mitochondria. Excessive MAO activation is also responsible for an increase in β- and γ-secretase expression10. Thus, not surprisingly, MAO inhibitors have been considered promising and attractive targets for the therapy of neurodegenerative diseases12,13.
Functional imaging of mitochondria in genetically confirmed retinal dystrophies using flavoprotein fluorescence
Published in Ophthalmic Genetics, 2022
Matthew W. Russell, Justin C. Muste, Kanika Seth, Madhukar Kumar, Collin A. Rich, Rishi P. Singh, Elias I. Traboulsi
Mitochondrial flavoproteins are proteins containing riboflavin derivatives that serve essential roles in mitochondrial electron transport (3,4). In a pro-oxidant environment, flavoproteins display properties of autofluorescence (FPF), emitting green light (520–540 nm) when excited by a blue spectrum light (455–470 nm) (6,7). The green emission signal can then be quantified and used as a direct marker of oxidative stress and mitochondrial dysfunction (8). FPF may be reported as intensity, a cumulative value reflecting global signal strength, and/or heterogeneity, which quantifies the variation of the relative intensity of points in the image. Together, these signals are meant to facilitate early disease detection for a given patient. Twelve peer reviewed clinical studies have demonstrated that FPF intensity and heterogeneity increase in various ocular pathologies including diabetic retinopathy, glaucoma, central serous chorioretinopathy, and AMD (8–14). Elner et al. examined FPF intensity in one patient with retinitis pigmentosa (RP) and found increased FPF intensity compared to a similarly aged control patient (12). However, this was a single case report, leaving the utility of FPF in patients with retinal dystrophies largely unknown.
Two cases of glutaric aciduria type II: how to differentiate from inflammatory myopathies?
Published in Acta Clinica Belgica, 2019
Meltem Koca, Abdulsamet Erden, Berkan Armagan, Alper Sari, Fatih Yildiz, Sevim Ozdamar, Umut Kalyoncu, Omer Karadag
Glutaric aciduria type II (GAII) or multiple acyl-CoA dehydrogenase deficiency (MADD) (OMIM #231,680) is an autosomal recessively inherited rare disorder of fatty acid and amino acid metabolisms. It results from the deficiency in anyone of three molecules: the alpha and beta subunits of electron transfer flavoprotein (ETFA and ETFB), and electron transfer flavoprotein dehydrogenase (ETFDH) [1]. In GAII, urine organic acid analysis demonstrates increased excretion of lactic, ethylmalonic, butyric, isobutyric, and isovaleric acids whereas it is the only organic acid whose concentration increases in GAI is glutaric acid.