Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Panic disorder is an anxiety disorder that can be treated by long-term administration of tricyclic antidepressants such as imipramine, monoamine oxidase inhibitors such as phenelzine, or the selective serotonin reuptake inhibitor (SSRI) antidepressants. Clinical data also indicate that some benzodiazepines, such as alprazolam, are effective antipanic agents, and that their therapeutic onset is faster than that of antidepressants. Benzodiazepines are well known for their action at GABA(A) receptors, and preclinical data indicate that imipramine and phenelzine also interfere with the GABAergic system. In addition some clinical data lend support to decreased benzodiazepine-sensitive receptor function in panic disorder patients. Using imipramine, phenelzine and alprazolam, we investigated, in rats, the possibility that the therapeutic efficacy of antipanic agents stems from the remodeling of GABAergic transmission in the pons-medulla region. Of the 12 GABA(A) receptor subunit (alpha 1--6, beta 1--3, gamma 1--3) steady-state mRNA levels investigated, we observed an increase in the levels of the alpha 3-, beta 1- and gamma 2-subunit transcripts with all three antipanic agents tested. The effects of imipramine and phenelzine on these subunits occurred after 21 days of treatment, while alprazolam effects were observed after 3 days of administration. Histochemical data suggest that the alpha 3 beta 1 gamma 2 subunits comprise a receptor subtype in the pons-medulla region. Therefore, we conclude that these molecular events parallel the therapeutic profile of the drugs examined. We further propose that these events may correspond to a remodeling of the GABA(A) receptor population, and may be useful markers for investigation of the antipanic properties of drugs.
Mol Psychiatry 2001 Jul
PMID:Common effects of chronically administered antipanic drugs on brainstem GABA(A) receptor subunit gene expression. 1144 24

Major changes in psychiatric phenotypes due to genetic factors are seldom the result of single gene polymorphisms, but more often the result of several genetic mechanisms. In this millennium article we discuss the notion that the expression of numerous candidate genes could be regulated by the same transcription factors, and that polymorphisms in transcription factor genes might explain some phenotypes. We describe recent results of studies on the biological marker thrombocyte monoamine oxidase (trbc MAO) and the transcription factor AP-2beta. Low levels of trbc MAO is associated with temperamental characteristics such as sensation seeking and impulsiveness, and the enzyme is genetically regulated by specific transcriptional mechanisms. Transcription factor AP-2beta is important for the development of midbrain structures and AP-2beta has several binding sites in the regulatory regions of genes encoding key proteins in the monoamine transmitter systems. We have recently shown AP-2beta to be linked to personality, binge-eating disorder, treatment with antidepressant drugs, and also to trbc MAO. Regardless of whether transcriptions factors, such as AP-2beta, regulate the expression of eg, the number of monoamine neurons or a variety of candidate genes within the monoamine systems, or both, we would like to emphasize the role of transcription factors, besides polymorphisms in monoaminergic candidate genes, when explaining inter-individual differences in temperament and psychiatric vulnerability.
Mol Psychiatry 2001 Sep
PMID:Genetic mechanisms of behavior--don't forget about the transcription factors. 1152 64

3,4-Dihydroxyphenylacetaldehyde (DOPAL) and 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL), the monoamine oxidase (MAO) metabolites of dopamine (DA) and norepinephrine (NE), respectively, are toxic to catecholamine (CA) neurons in vitro and in vivo. DOPEGAL generates a free radical and activates mitochondrial permeability transition, a mechanism implicated in neuron death. To determine if DOPAL and other DA metabolites generate the hydroxyl radical in the presence of H(2)O(2), we used HPLC-EC to detect salicylate hydroxylation products. To determine the relative reducing capacity of DOPAL and DOPEGAL we used cyclic voltammetry to measure their reduction potentials. Results indicate that DOPAL, but not DOPEGAL, DA or other DA metabolites, generates hydroxyl radicals. Atomic absorption spectroscopy and heavy metal screening indicate that this result is not due to contamination of DOPAL with iron or other heavy metals. DOPAL reduction potential (161 mV) is lower than that of DOPEGAL (235 mV). DOPAL is present in human substantia nigra. The implications of these findings to CA neuronal death in degenerative brain diseases are discussed.
Brain Res Mol Brain Res 2001 Sep 10
PMID:3,4-Dihydroxyphenylacetaldehyde and hydrogen peroxide generate a hydroxyl radical: possible role in Parkinson's disease pathogenesis. 1153 32

Hydrogen peroxide generated by monoamine oxidase (MAO)-mediated deamination of biogenic amines has been implicated in cell signaling and oxidative injury. Because the pulmonary endothelium is a site of metabolism of monoamines present in the venous return, this brings into question a role for MAO in hyperoxic lung injury. The objective of this study was to evaluate the O(2) dependency of the MAO reaction in the lung. To this end, we measured the pulmonary venous effluent concentrations of the MAO substrate [(14)C]phenylethylamine and its metabolite [(14)C]phenylacetic acid after the bolus injection of either phenylethylamine or phenylacetic acid into the pulmonary artery of perfused rabbit lungs over a range of PO(2) values from 16 to 518 Torr. The apparent Michaelis constant for O(2) was approximately 18 microM, which is more than an order of magnitude less that measured for purified MAO. The results suggest a minimal influence of high O(2) on MAO activity in the normal lung and demonstrate the importance of measuring reaction kinetics in the intact organ.
Am J Physiol Lung Cell Mol Physiol 2001 Oct
PMID:Oxygen dependency of monoamine oxidase activity in the intact lung. 1155 1

Lysyl oxidase (LOX), a copper-containing amine oxidase, belongs to a heterogeneous family of enzymes that oxidize primary amine substrates to reactive aldehydes. LOX has been traditionally known for one function, the extracellular catalysis of lysine-derived cross-links in fibrillar collagens and elastin. More recently, diverse roles have been attributed to lysyl oxidase and these novel activities cover a spectrum of diverse biological functions such as developmental regulation, tumor suppression, cell motility, and cellular senescence. Lysyl oxidase has also been shown to have both intracellular and intranuclear locations. The multifunctional properties of lysyl oxidase (LOX) and our recent discovery of three novel members of this amine oxidase family, LOX-like (LOXL), LOXL2, and LOXL3, indicate the possibility that these varied functions are performed in both intracellular and extracellular environments by individual novel members of the LOX amine-oxidase family. Structural similarities of the highly conserved copper-binding and lysyl-tyrosylquinone cofactor sites among the LOX and LOX-like proteins may result in similar amine oxidase activities. However, specific novel functions, such as a potential role in cell adhesion and cell growth control, will be determined by other, conserved domains such as the cytokine receptor-like domain that is shared by all LOXs and by multiple scavenger receptor cysteine-rich (SRCR) domains present in LOXL2 and LOXL3. Furthermore, these functions may be carried out in a temporally and spatially regulated fashion.
Prog Nucleic Acid Res Mol Biol 2001
PMID:Lysyl oxidases: a novel multifunctional amine oxidase family. 1164 59

Copper chaperones are small cytoplasmic proteins that bind intracellular copper (Cu) and deliver it to Cu-dependent enzymes such as cytochrome oxidase, superoxide dismutase, and amine oxidase. Copper chaperones are similar in sequence and structure to the Cu-binding heavy metal-associated (HMA) domains of Cu-transporting ATPases (Cu-ATPases), and the genes for copper chaperones and Cu-ATPases are often located in the same operon. Phylogenetic analysis shows that Cu chaperones and HMA domains of Cu-ATPases represent ancient and distinct lineages that have evolved largely independently since their initial separation. Copper chaperone-Cu-ATPase operons appear to have evolved independently in different prokaryotic lineages, probably due to a strong selective pressure for coexpression of these genes.
J Mol Evol 2001 Dec
PMID:Independent evolution of heavy metal-associated domains in copper chaperones and copper-transporting atpases. 1167 22

Isatin, an endogenous monoamine oxidase (MAO) inhibitor, has been found in mammalian tissues. We previously reported that exogenously administered isatin significantly increased acetylcholine (ACh) and dopamine (DA) levels in the rat striatum. In order to elucidate the relationship between isatin and Parkinson's disease, we measured urinary isatin excretions in patients with Parkinson's disease using a newly developed HPLC-UV method. The recovery of this assay was approximately 102.3% at a range from 2 to 50 nmol/ml. The Coefficient of Variance (CV) for the determination at this range was approximately 2.5% for intra-assay and 6.2% for inter-assay, respectively. There was no significant difference in urinary isatin excretion between data from men and women in healthy control. The value in young age group (19-35 years old) was not significantly different compared with that of the older age group (54-84 years old). Urinary isatin levels in patients with Parkinson's disease tended to increase in accordance to the Hoehn and Yahr criteria. This is the first study in which a significant increase in urinary isatin excretion was observed at Stage III, IV and V in patients with Parkinson's disease. Urinary isatin concentrations in drug-treated patients with Parkinson's disease (at Stage I and II) tended to decrease compared with those of patients without medication. These results demonstrated that urinary isatin excretion may serve as an endogenous diagnostic marker for the clinical severity of Parkinson's disease.
Res Commun Mol Pathol Pharmacol
PMID:Urinary isatin concentrations in patients with Parkinson's disease determined by a newly developed HPLC-UV method. 1175 76

This study was conducted to identify enzyme systems eventually catalysing a local cerebral metabolism of citalopram, a widely used antidepressant of the selective serotonin reuptake inhibitor type. The metabolism of citalopram, of its enantiomers and demethylated metabolites was investigated in rat brain microsomes and in rat and human brain mitochondria. No cytochrome P-450 mediated transformation was observed in rat brain. By analysing H2O2 formation, monoamine oxidase A activity in rat brain mitochondria could be measured. In rat whole brain and in human frontal cortex, putamen, cerebellum and white matter of five brains monoamine oxidase activity was determined by the stereoselective measurement of the production of citalopram propionate. All substrates were metabolised by both forms of MAO, except in rat brain, where monoamine oxidase B activity could not be detected. Apparent Km and Vmax of S-citalopram biotransformation in human frontal cortex by monoamine oxidase B were found to be 266 microM and 6.0 pmol min(-1) mg(-1) protein and by monoamine oxidase A 856 microM and 6.4 pmol min(-1) mg(-1) protein, respectively. These Km values are in the same range as those for serotonin and dopamine metabolism by monoamine oxidases. Thus, the biotransformation of citalopram in the rat and human brain occurs mainly through monoamine oxidases and not, as in the liver, through cytochrome P-450.
Mol Psychiatry 2002
PMID:In vitro biotransformation of the selective serotonin reuptake inhibitor citalopram, its enantiomers and demethylated metabolites by monoamine oxidase in rat and human brain preparations. 1184 Mar 11

Binary quantitative structure-activity relationship (QSAR) is an approach for the analysis of high throughput screening (HTS) data by correlating structural properties of compounds with a "binary" expression of biological activity (1 = active and 0 = inactive) and calculating a probability distribution for active and inactive compounds in a training set. Successfully deriving a predictive binary or any QSAR model largely depends on the selection of a preferred set of molecular descriptors that can capture the chemico-biological interaction for a particular biological target. In this study, a genetic algorithm (GA) was applied as a variable selection method in binary QSAR analysis. This GA-based variable selection method was applied to the analysis of three diverse sets of compounds, estrogen receptor (ER) ligands, carbonic anhydrase II inhibitors, and monoamine oxidase (MAO) inhibitors. Out of a variable pool of 150 molecular descriptors, predictive binary QSAR models were obtained for all three sets of compounds within a reasonable number of GA generations. The results indicate that the GA is a very effective variable selection approach for binary QSAR analysis.
J Mol Graph Model 2002 Jan
PMID:Enhancement of binary QSAR analysis by a GA-based variable selection method. 1185 34

The human cardiac nervous system consists of a sympathetic and a parasympathetic branch with (-)-norepinephrine and acetylcholine as the respective endogenous neurotransmitters. Dysfunction of the cardiac nervous system is implicated in various types of cardiac disease, such as heart failure, myocardial infarction and diabetic autonomic neuropathy. In vivo assessment of the distribution and function of cardiac sympathetic and parasympathetic neurones with positron emission tomography (PET) and single-photon emission tomography (SPET) can be achieved by means of a number of carbon-11-, fluorine-18-, bromine-76- and iodine-123-labelled tracer molecules. Available tracers for mapping sympathetic neurones can be divided into radiolabelled catecholamines, such as 6-[18F]fluorodopamine, (-)-6-[18F]fluoronorepinephrine and (-)-[11C]epinephrine, and radiolabelled catecholamine analogues, such as [123I]meta-iodobenzylguanidine, [11C]meta-hydroxyephedrine, [18F]fluorometaraminol, [11C]phenylephrine and meta-[76Br]bromobenzylguanidine. Resistance to metabolism by monoamine oxidase and catechol-O-methyl transferase simplifies the myocardial kinetics of the second group. Both groups of compounds are excellent agents for an overall assessment of sympathetic innervation. Biomathematical modelling of tracer kinetics is complicated by the complexity of the steps governing neuronal uptake, retention and release of these agents as well as by their high neuronal affinity, which leads to partial flow dependence of uptake. Mapping of cardiac parasympathetic neurones is limited by a low density and focal distribution pattern of these neurones in myocardium. Available tracers are derivatives of vesamicol, a molecule that binds to a receptor associated with the vesicular acetylcholine transporter. Compounds like (-)-[18F]fluoroethoxybenzovesamicol display a high degree of non-specific binding in myocardium which restricts their utility for cardiac neuronal imaging.
Eur J Nucl Med Mol Imaging 2002 Mar
PMID:PET and SPET tracers for mapping the cardiac nervous system. 1200 20


<< Previous 1 2 3 4 5 6 7 8 9 10