ABSTRACT
Furin belongs to serine intracellular Ca2+-dependent endopeptidases of the subtilisin family, also known as proprotein convertase (PC). Human furin is synthesized as zymogen with a molecular weight of 104 kDà, which is then activated by autocatalytic in two stages. This process can occur when zymogen migrates from the endoplasmic reticulum to the Golgi apparatus, where a large part of furin is accumulated. The molecular weigh t of the active furin is 98 kDà. Furin relates to enzymes with a narrow substrate specificity: it hydrolyzes peptide bonds at the site of paired basic amino acids and furin activity exhibits in a wide pH range 5-8. Its main biological function is activation of the functionally important protein precursors. It is accompanied by the launch of a cascade of reactions, which lead to appearance of biologically active molecules involved in realization of specific biological functions both in normal and in some patologicheskih processes. Furin substrates are biologically important proteins such as enzymes, hormones, growth factors and differentiation, receptors, adhesion proteins, proteins of blood plasma. Furin plays an important role in the development of processes such as proliferation, invasion, cell migration, survival, maintenance of homeostasis, embryogenesis, as well as the development of a number of pathologies, including cardiovascular, oncologic and neurodegenerative diseases. Furin and furin-like proprotein convertases participate as key factors in the realization of the regulatory functions of proteolytic enzymes, the value of which is currently being evaluated as most important in comparison with the degradative function of proteases.
Subject(s)
Cardiovascular Diseases/enzymology , Enzyme Precursors/metabolism , Furin/metabolism , Neoplasm Proteins/metabolism , Neoplasms/enzymology , Neurodegenerative Diseases/enzymology , Animals , Enzyme Activation , Humans , Hydrogen-Ion Concentration , Neoplasm Invasiveness , Neoplasms/pathologyABSTRACT
The paper describes the physiological effects of various biogenic amines, their occurrence in the body, and degradation. It outlines the present views of diversity of flavin adenine dinucleotide-dependent and semicarbazide-sensitive amine oxidases. Methods for preparation of various tissue extracts and spectrophotometric and radiation techniques for determination of the activity of these enzymes, by using various substrates, are described.
Subject(s)
Amine Oxidase (Copper-Containing)/metabolism , Biogenic Amines/metabolism , Monoamine Oxidase/metabolism , Amine Oxidase (Copper-Containing)/chemistry , Animals , Biogenic Amines/chemistry , Monoamine Oxidase/chemistry , RatsABSTRACT
An aim of the paper was to study some biochemical parameters of drug-naïve patients with the first episode of schizophrenia. Activities of platelet monoaminooxidase (MAO) and semicarbazide, a sensitive blood serum aminooxidase (BSA), levels of middle-sized molecules (MSM) and malonic dialdehyde (MDA), parameters of functional state of serum albumin were assessed in 16 patients. Severity of symptoms in patients with the first episode of schizophrenia was assessed as moderate (PANSS scores 73.1+/-12.5) before the treatment. The increase of MAO by 107%, reduction of BSA by 29% and increase of MSM level by 140% was found in patients compared to controls (p<0.01). The study of other biochemical (MDA level) and biophysical (effective albumin concentration) parameters did not yield unequivocal results. It has been suggested that MAO and BSA are integral components of pathogenetic mechanisms in patients with the first episode of schizophrenia.
Subject(s)
Blood Platelets/enzymology , Monoamine Oxidase/blood , Schizophrenia/metabolism , Adult , Data Interpretation, Statistical , Female , Humans , Lipid Peroxidation , Male , Malondialdehyde/blood , Monoamine Oxidase/metabolism , Patient Selection , Regression Analysis , Schizophrenia/blood , Schizophrenia/diagnosis , Schizophrenia/enzymology , Serum Albumin/analysisABSTRACT
Seasonal variations of recovery of liver monoamine oxidase activity were studied in different subcellular fractions after administration of a large dose of pargyline in vivo. It was shown that the recovery of cytosolic MAO differs greatly from the membrane bound forms in the rate of reconstitution of its activity upon irreversible inhibition in vivo. Alcoholization leads to a decrease of the rate of recovery of only the membrane-bound but not a cytosolic MAO B forms in rat liver.
Subject(s)
Alcoholism/enzymology , Liver/enzymology , Monoamine Oxidase/biosynthesis , Animals , Enzyme Reactivators/pharmacology , Monoamine Oxidase Inhibitors/pharmacology , Pargyline/pharmacology , Rats , Rats, Wistar , Seasons , Subcellular Fractions/enzymologyABSTRACT
The study experimentally assessed the approach proposed by the authors to lower alcohol motivation, which involves enhancement of a specific immunity at the stage of alcoholization when acetaldehydemodified ethanol exchange enzymes [alcohol dehydrogenase (ADH)] and acetaldehyde dehydrogenase may be expected to occur. Omega-3 polyunsaturated fatty acid (PUFA) drugs enhance the formation of autoantibodies to modified ADH and decrease the activity of ADH in the stomach and liver. At the same time, PUFA drugs can, under certain conditions, produce an anti-alcoholic activity and a positive effect on the psychoemotional status of animals after the ethanol deprivation period.
Subject(s)
Alcohol Dehydrogenase/drug effects , Antibodies/blood , Fatty Acids, Omega-3/pharmacology , Motivation , Alcohol Dehydrogenase/immunology , Aldehyde Oxidoreductases/drug effects , Aldehyde Oxidoreductases/immunology , Animals , Antibodies/drug effects , Behavior, Animal/drug effects , Ethanol/metabolism , Liver/drug effects , Liver/enzymology , Male , Pharmaceutical Preparations , Rats , Stomach/drug effects , Stomach/enzymologyABSTRACT
Experimental results have demonstrated a significant decrease in the level of alcohol consumption by albino rats immunized with heterologous horse alcohol dehydrogenase. The role of ADH epitopes 9-14, 93-115, and 265-276 in this phenomenon was examined, and it was established that the latter sequence (265-276) plays the biggest role. The inhibition of ADH activity in the adrenals of immunized rats was much higher compared to the liver. We propose a hypothesis that the effect of alcohol dehydrogenase on alcohol consumption is connected with its role in catecholamine metabolism.
Subject(s)
Adrenal Glands/immunology , Alcohol Dehydrogenase/immunology , Alcohol Drinking/immunology , Adrenal Glands/enzymology , Alcohol Drinking/prevention & control , Animals , Enzyme Activation/immunology , Epitopes/immunology , Immunization , Male , Rats , Rats, WistarABSTRACT
The sensitivity of mitochondrial and cytosolic monoamine oxidase (MAO) activities to inhibition by specific irreversible inhibitors was investigated. There were no significant differences in the sensitivity of MAO A and MAO B activities of these fractions to selective inhibitors. However, in vivo administration of pargyline caused a much more potent inhibition of cytosolic MAO than the mitochondrial enzymes. This suggests that cytosolic MAO activity does not represent an artifact (e.g. a product of proteolytic degradation) appearing after tissue homogenisation. The higher sensitivity of cytosolic MAO to inhibitors also points to different routes for pargyline to inhibit MAO in these subcellular fractions.
Subject(s)
Liver/enzymology , Mitochondria, Liver/enzymology , Monoamine Oxidase Inhibitors/pharmacology , Monoamine Oxidase/metabolism , Pargyline/pharmacology , Selegiline/pharmacology , Animals , Cytosol/enzymology , Isoenzymes/antagonists & inhibitors , Kinetics , Male , Rats , Reproducibility of Results , Substrate SpecificityABSTRACT
The range of the biochemical reactions which can be catalyzed by ADH I and ADH IV is extremely wide. The most characterized functions of these enzymes are protection against excess endogenous acetaldehyde, products of lipid peroxidation, exogenous alcohols and some xenobiotics. It was found also that ADH I and ADH IV are important members of the enzyme system synthesizing retinoic acid (especially during embryogenesis). They can oxidize some steroids and participate in bioamine and prostaglandin metabolism but so far the extent of their contribution to the latter processes is under discussion. Recent data suggest a correlation between the activity of ADH I in some organs and fine physiological processes including behavior regulation and craving for alcohol in albino rats.
Subject(s)
Alcohol Dehydrogenase/metabolism , Ethanol/metabolism , Animals , Humans , Lipid Peroxidation , Neurotransmitter Agents/metabolism , Steroids/metabolism , Substance Withdrawal Syndrome/enzymology , Vitamin A/metabolismABSTRACT
Cytosolic and particulate monoamine oxidases have been isolated. Cytosolic preparation was free from mitochondrial and microsomal contaminations and also ribosome-bound MAO molecules. Cytosolic MAO had higher affinity for phenylethylamine and exhibited higher sensitivity to acetylenic inhibitors than the mitochondrial enzyme.
Subject(s)
Cytosol/enzymology , Liver/enzymology , Monoamine Oxidase/metabolism , Animals , Monoamine Oxidase Inhibitors/pharmacology , RatsABSTRACT
A series of pirlindole analogues were tested as inhibitors of monoamine oxidase A and B. Although we did not find strict dependence between 3D-size of molecules and their inhibitory potency, rigid analogues exhibited potent and selective inhibition of MAO-A. They have 3D size limits of 13 angstroms (length) x 7 angstroms (height) x 4.4 angstroms (widths). Besides MAO-A inhibition flexible analogues also demonstrated potent inhibition of MAO-B. Five compounds were studied as inhibitors of purified human liver MAO-A. Their inhibitory potencies coincided with those obtained using rat liver mitochondrial MAO-A. Each compound induced changes in the spectrum of MAO-A but these did not correlate with the flexibility of the derivative. It is also possible that the oxygen bridge introduced with the flexibility might influence spectral patterns.
Subject(s)
Carbazoles/pharmacology , Computer Simulation , Models, Molecular , Monoamine Oxidase Inhibitors/pharmacology , Monoamine Oxidase/drug effects , Animals , Carbazoles/chemistry , Humans , Mitochondria, Liver/drug effects , Mitochondria, Liver/enzymology , Monoamine Oxidase/metabolism , Monoamine Oxidase Inhibitors/chemistry , Placenta/drug effects , Placenta/enzymology , RatsABSTRACT
A series of pyrazinocarbazoles, analogues of short acting antidepressant pirlindole (2,3,3a,4,5,6-hexahydro-8-methyl-1H-pyrazino[3,2,1-j,k]carbazole hydrochloride), were tested as inhibitors of monoamine oxidase A (MAO-A) and B (MAO-B). Rigid analogues exhibited potent and selective inhibition of MAO-A and have size limits (X:Y:Z) of 13.0 x 7.0 x 4.4 A. Besides MAO-A inhibition flexible analogues also demonstrated potent inhibition of MAO-B and in contrast to rigid analogues their inhibitory activity did not show the dependence on these sizes. The qualitative information (steric and electrostatic coefficients) from the 3D-QSAR with CoMFA models for MAO-A and -B are different, and this information can be used to determine the structural features influencing inhibitor selectivity.
Subject(s)
Carbazoles/chemistry , Carbazoles/pharmacology , Monoamine Oxidase Inhibitors/chemistry , Monoamine Oxidase Inhibitors/pharmacology , Monoamine Oxidase/chemistry , Animals , In Vitro Techniques , Isoenzymes/chemistry , Isoenzymes/metabolism , Mitochondria, Liver/drug effects , Mitochondria, Liver/enzymology , Models, Molecular , Monoamine Oxidase/metabolism , Protein Conformation , Rats , Structure-Activity RelationshipSubject(s)
Amine Oxidase (Copper-Containing) , Blood Proteins/antagonists & inhibitors , Brain/metabolism , Memory/physiology , Oxidoreductases Acting on CH-NH Group Donors/antagonists & inhibitors , Animals , Avoidance Learning/physiology , Benzylamine Oxidase/blood , Blood Proteins/immunology , Brain/enzymology , Brain/immunology , Brain/ultrastructure , Cattle , Dopamine/metabolism , Freund's Adjuvant/immunology , Male , Mitochondria/enzymology , Mitochondria/metabolism , Monoamine Oxidase/blood , Norepinephrine/metabolism , Oxidoreductases Acting on CH-NH Group Donors/blood , Oxidoreductases Acting on CH-NH Group Donors/immunology , Rats , Serotonin/metabolism , VaccinationABSTRACT
Addition of 30mM glutamate to the culture medium decreased growth of rat glioma C6 cells accompanied by a decrease of DNA synthesis and an increase of lactate dehydrogenase (LDH) detected in the conditioned medium. The presence of 1 microM deprenyl attenuated the glutamate effect on cell growth only during the first 24-48 h incubation and had a minor influence on the glutamate-induced decrease of DNA synthesis. Clorgyline (1 microM) potentiated glutamate-induced DNA synthesis during the first 24 h incubation without significant influence on the cell growth. Deprenyl slightly attenuated the glutamate-induced LDH increase during 24 h incubation but potentiated the glutamate effect at 96 h. Clorgyline decreased the glutamate influence at 24 h and especially 96 h. All these effects were observed in the absence of exogenous monoamines in the culture medium. These results suggest that in transformed cells monoamine oxidase (MAO) inhibitors may influence processes of cell death via MAO-independent mechanisms.
Subject(s)
Cell Survival/drug effects , Clorgyline/pharmacology , Glutamic Acid/toxicity , Monoamine Oxidase Inhibitors/pharmacology , Neurotoxins/toxicity , Selegiline/pharmacology , Animals , Cell Division/drug effects , Cell Line, Transformed , DNA, Neoplasm/biosynthesis , Glioma , Kinetics , L-Lactate Dehydrogenase/analysis , Rats , Time Factors , Tumor Cells, CulturedABSTRACT
The results of investigation concerning both total and cerebral catecholamine metabolism indices in 78 patients with amyotrophic lateral sclerosis (ALS) are presented. The considerable elevation of both blood and liquor norepinephrine level as well as of blood epinephrine concentration was observed together with acute decrease of platelet MAO B activity. The conclusion was made about the participation of catecholamines in exitotoxic mechanisms of motor neurons systems death which was quite characteristic for ALS development. A short literary review was presented concerning the role of neurotransmitters in regulation of motor functions. The neurochemical disturbances which may result in release of exitotoxic mechanisms of ALS were considered too. The consideration of data obtained as well as the analysis of modern conceptions of ALS pathogenesis enable both to determine some ways of ALS pathogenetic therapy and to define the basic directions of further investigations.
Subject(s)
Amyotrophic Lateral Sclerosis/metabolism , Neurotransmitter Agents/analysis , Adult , Aged , Catecholamines/analysis , Chromatography, High Pressure Liquid , Chronic Disease , Female , Humans , Male , Middle AgedABSTRACT
Indole and isatin (2,3-dioxindole) analogues were studied as inhibitors of MAO-A and B. They exhibited reversible and competitive MAO inhibition. Three dimensional structures of the compounds tested were constructed and minimized using PC-based molecular graphic software. The QSAR analysis revealed the requirement of co-planar structure of substituents at C2 and C3 of indole ring for selective MAO-A inhibition, whilst type of bond was less essential. The presence of hydroxy group at C5 of isatin increased selectivity of MAO-A inhibition, however simultaneous insertion of substituents into both positions of indole ring (5-hydroxy-2-phenylindole) led to a decrease of MAO-A inhibition. The planar molecules demonstrating potent MAO-A inhibition have the average sizes 7 A in length and 6 A in width. The MAO B inhibition also depended on the sizes of planar molecules however distribution of electron density in the molecules was another precondition for the selective inhibition of the enzyme.
Subject(s)
Indoles/pharmacology , Mitochondria/enzymology , Monoamine Oxidase Inhibitors/pharmacology , Monoamine Oxidase/metabolism , Animals , Humans , Indoles/chemistry , Indoles/metabolism , Isatin/analogs & derivatives , Isatin/chemistry , Isatin/metabolism , Isatin/pharmacology , Kinetics , Molecular Structure , Monoamine Oxidase Inhibitors/chemistry , Monoamine Oxidase Inhibitors/metabolism , Rats , Structure-Activity RelationshipABSTRACT
The art-of-the-state and possible perspectives for studies of the properties of amine oxidases which are medically significant are briefly outlined. Due to the studies conducted at the Research Institute of Biomedical Chemistry of the Russian Academy of Medical Sciences, the authors discuss the results of studies of the following three problems: 1) modified catalytic properties of amine oxidases in experimental intoxications and abnormalities; 2) natural modulators of amine oxidases; 3) synthetic modulators of amine oxidases.
Subject(s)
Monoamine Oxidase Inhibitors/therapeutic use , Oxidoreductases/metabolism , Amine Oxidase (Copper-Containing)/metabolism , Animals , Antidepressive Agents/therapeutic use , Antioxidants/therapeutic use , Brain/enzymology , Brain/metabolism , Carbazoles/therapeutic use , Cerebrospinal Fluid/enzymology , Cerebrospinal Fluid/metabolism , Dicarbethoxydihydrocollidine/analogs & derivatives , Dicarbethoxydihydrocollidine/therapeutic use , Herbicides/poisoning , Humans , In Vitro Techniques , Mental Disorders/drug therapy , Monoamine Oxidase/metabolism , Oxidoreductases Acting on CH-NH Group Donors/metabolism , Poisoning/drug therapy , Rats , gamma-Aminobutyric Acid/metabolismABSTRACT
Langmuir-Blodgett (LB) films of monoamine oxidase (MAO) have been formed on the surface f a polypropylene membrane using amphiphilic polyelectrolytes. The enzyme activity of such protein-polyelectrolyte films was measured by a Clark electrodes. It was shown that in LB films thus formed the use of amphiphilc polyelectrolytes, MAO activity was higher than in polyelectrolyte-free LB films. Immobilization of MAO with branched polyethylenimine modified on 12% by laurylchain led to pronounced changes in its catalytic properties. The dependence of the enzyme's kinetic parameters on amphiphilic polyelectrolyte structures was discussed. (c) 1994 John Wiley & Sons, Inc.
ABSTRACT
The novel antidepressant tetrindole (2,3,3a,4,5,6-hexahydro-8-cyclohexyl-1H[3,2,1-j,k] carbazole) was found to be a selective inhibitor of monoamine oxidase A (MAO A). In vitro it inhibited rat brain mitochondrial MAO A in a competitive manner with Ki value of 0.4 microM. A 60 min preincubation did not change the competitive mode of interaction between enzyme and tetrindole (Ki value was 0.27 microM). The inhibition of rat brain mitochondrial MAO B was of mixed type with Ki value of 110 microM. Dilution or dialysis of mitochondrial suspension did not restore MAO A activity after inhibition by tetrindole both in vitro and in vivo, whereas inhibition of MAO B in vitro was completely reversible. Oral administration of tetrindole inhibited rat brain and liver mitochondrial MAO A by 80% within 0.5-1 hr and the onset of recovery of enzyme activity became evident after 24 hr. A small inhibition of MAO B (-20-30%) was observed in isolated brain and liver mitochondria within 1-6 hr and enzyme activity had completely recovered after 16 hr. The data obtained indicate that antidepressant activity of tetrindole may be explained by selective inhibition of MAO A, however an apparent discrepancy between competitive manner of MAO A inhibition in vitro and poor recovery of enzyme activity in vivo does not allow us to decide whether tetrindole is a "tight-binding" reversible inhibitor or a selective irreversible inhibitor of MAO A.
Subject(s)
Antidepressive Agents/pharmacology , Carbazoles/pharmacology , Monoamine Oxidase Inhibitors/pharmacology , Animals , Brain/drug effects , Brain/enzymology , Carbazoles/administration & dosage , Kinetics , Male , Mitochondria, Liver/drug effects , Mitochondria, Liver/enzymology , RatsABSTRACT
The effect on deamination of serotonine, dopamine, tiramine and 2-phenylamine of benzamide derivatives befol, moclobemide and LIS-641 was studied. Befol and moclobemide are inhibitors of serotonine deaminating activity of MAO. The different sensitivity of this activity to the effect of the benzamide derivatives in beef or rat brain and human placenta was noted. The inhibition was more distinct in tissue homogenate than in corresponding mitochondrial fractions.
Subject(s)
Antidepressive Agents/pharmacology , Benzamides/pharmacology , Monoamine Oxidase/drug effects , Morpholines/pharmacology , Animals , Blood Platelets/drug effects , Blood Platelets/enzymology , Brain/drug effects , Brain/enzymology , Cattle , Female , Humans , Mitochondria/drug effects , Mitochondria/enzymology , Moclobemide , Monoamine Oxidase/metabolism , Placenta/drug effects , Placenta/enzymology , RatsABSTRACT
Effects of befol and moklobemide on thyramine-, serotonin- and 2-phenyl ethylamine deaminase activities of mitochondrial monoamine oxidase from bovine truncus cerebri were studied. These drugs are reversible noncompetitive inhibitors of the enzyme not requiring preincubation. They inhibited most effectively the serotonin deaminase activity as compared with phenyl ethylamine deaminase activity, however they should not be concerned with typical inhibitors of monoamine oxidases of the A type as inhibition of thyramine deaminase activity was not found.