Gene/Protein Disease Symptom Drug Enzyme Compound
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Severe psychiatric disorders such as schizophrenia, bipolar disorder and major depressive disorder are brain diseases of unknown origin. No biological marker has been documented at the pathological, cellular, or molecular level, suggesting that a number of complex but subtle changes underlie these illnesses. We have used proteomic technology to survey postmortem tissue to identify changes linked to the various diseases. Proteomics uses two-dimensional gel electrophoresis and mass spectrometric sequencing of proteins to allow the comparison of subsets of expressed proteins among a large number of samples. This form of analysis was combined with a multivariate statistical model to study changes in protein levels in 89 frontal cortices obtained postmortem from individuals with schizophrenia, bipolar disorder, major depressive disorder, and non-psychiatric controls. We identified eight protein species that display disease-specific alterations in level in the frontal cortex. Six show decreases compared with the non-psychiatric controls for one or more diseases. Four of these are forms of glial fibrillary acidic protein (GFAP), one is dihydropyrimidinase-related protein 2, and the sixth is ubiquinone cytochrome c reductase core protein 1. Two spots, carbonic anhydrase 1 and fructose biphosphate aldolase C, show increase in one or more diseases compared to controls. Proteomic analysis may identify novel pathogenic mechanisms of human neuropsychiatric diseases.
Mol Psychiatry 2000 Mar
PMID:Disease-specific alterations in frontal cortex brain proteins in schizophrenia, bipolar disorder, and major depressive disorder. The Stanley Neuropathology Consortium. 1082 41

A classification of diuretics mainly comprises mercurials; carbonic anhydrase inhibitors, thiazide diuretics, loop diuretics, inhibitors of renal epithelial Na+ channels and antagonists of mineralocorticoid receptors. We studied in this paper the relationship between diuretics and carbonic anhydrase (CA). Our in vitro and in vivo results show that all diuretics inhibit carbonic anhydrase II and renal CA IV. Further, our data show that they also inhibit epithelial cell CA in the renal tubules. The changes in intracellular pH (pHi) induced by these diuretics through CA inhibition would influence: a) the coupling to their receptors affecting information transmission to the epithelial cells of renal tubules as well as diuretic response; b) the decrease of Na+ exchanger (thiazide), of Na+ - K+ - 2Cl- relation (loop diuretics), Na+ channel blocking in distal and collecting tubules (amiloride, triamterene), as well as the antagonism between spironolactone and aldosterone at the mineralocorticoid receptor level, suggest that this competition might also be produced on CA II and on renal CA IV, which, in turn, could be influenced by pH-induced changes, the binding of the diuretic to its membrane receptor as well as the activity of the brush membrane or cytosolic pump. Furosemide and indapamide, diuretics known to have vasodilating effects, induce the fall of blood pressure that parallels the decrease of CA I activity. These results show the involvement of CA in the mechanism of action of the diuretics and in their actions associated with vasodilating effects. pH changes resulting from the action of CA contribute to the action of diuretics. All diuretics inhibit CA isozymes.
Res Commun Mol Pathol Pharmacol 1999
PMID:The inhibitory effect of diuretics on carbonic anhydrases. 1095 27

Water has been recognized as one of the major structuring factors in biological macromolecules. Indeed, water clusters influence many aspects of biological function, and the water-protein interaction has long been recognized as a major determinant of chain folding, conformational stability, internal dynamics, binding specificity and catalysis. I discuss here several themes arising from recent progress in understanding structural aspects of 'direct' and 'indirect' ligands in terms of enzyme-substrate interactions, and the role of water bridges in enzyme catalysis. The review also attempts to illuminate issues relating to efficiency, through solvent interactions associated with enzymic specificity, and versatility. Over the years, carbonic anhydrase (CA; carbonate hydrolyase, EC 4.2.1.1) has played a significant role in the continuing delineation of principles underlying the role of water in enzyme reactions. As a result of its pronounced catalytic power and robust constitution CA was transformed into a veritable 'laboratory' in which active site mechanisms were rigorously tested and explored.
Cell Mol Life Sci 2000 Jul
PMID:Water in enzyme reactions: biophysical aspects of hydration-dehydration processes. 1096 41

The crystal structures of l-fuculose-1-phosphate aldolase (FucA) with and without a ligated analogue of dihydroxyacetone phosphate (DHAP) and of a number of active center mutants have resulted in a model of the catalytic mechanism. This model has now been confirmed by structural analyses of further mutations at the zinc coordination sphere and at the phosphate site. In addition, these mutants have revealed new aspects of the catalysis: the hydroxyl group of Tyr113' (from a neighboring subunit), which sits just outside the zinc coordination sphere, steers DHAP towards a productive binding mode at the zinc ion; Glu73 contacts zinc in between the two ligand positions intended for the DHAP oxygen atoms and thus avoids blocking of these positions by a tetrahedrally coordinated hydroxy ion; the FucA polypeptide does not assume its minimum energy state but oscillates between two states of elevated energy as demonstrated by a mutant in a minimum energy state. The back and forth motion involves a mobile loop connecting the phosphate site with intersubunit motions and thus with the Brownian motion of the solvent. The phosphate group is bound strongly at a given distance to the zinc ion, which prevents the formation of too tight a DHAP:zinc complex. This observation explains our failure to find mutants that accept phosphate-free substitutes for DHAP. The FucA zinc coordination sphere is compared with that of carbonic anhydrase.
J Mol Biol 2000 Nov 03
PMID:Structures of l-fuculose-1-phosphate aldolase mutants outlining motions during catalysis. 1105 89

The occurrence, localization and response to environmental salinity of carbonic anhydrase (CA) activity were studied in all of the gills of the euryhaline crab Chasmagnathus granulata from Mar Chiquita coastal lagoon (Buenos Aires Province, Argentina). CA activity in all gills appeared to be dependent on salinity. The pattern of distribution of CA activity among gills was different upon transition of C. granulata from osmoionoconformity (more uniform distribution) to hyperregulation (highest activity in posterior gills 6-8). Upon abrupt salinity change a differential response of CA activity occurred among gills which could suggest a differential role of CA in ion transport process in different gills of this crab. Furthermore, CA activity in anterior and posterior gills was found in cytosolic and microsomal fractions, although highest activity appeared to be membrane-associated. Both pools of CA were also strongly influenced by salinity and very sensitive to sulfonamide acetazolamide. The results suggest a differential participation of branchial CA in ionoregulatory mechanisms of C. granulata.
Comp Biochem Physiol B Biochem Mol Biol 2000 Sep
PMID:Branchial carbonic anhydrase (CA) of gills of Chasmagnathus granulata (Crustacea Decapoda). 1112 55

Short chain fatty acids (SCFA) stimulate colonic Na+ absorption and inhibit cAMP and cGMP-mediated Cl- secretion. It is uncertain whether SCFA have equivalent effects on absorption and whether SCFA inhibition of Cl- secretion involves effects on mucosal enzymes. Unidirectional Na+ fluxes were measured across stripped colonic segments in the Ussing chamber. Enzyme activity was measured in cell fractions of scraped colonic mucosa. Mucosal 50 mM acetate, propionate, butyrate and poorly metabolized isobutyrate stimulated proximal colon Na+ absorption equally (300%). Neither 2-bromo-octanoate, an inhibitor of beta-oxidation, nor carbonic anhydrase inhibition affected this stimulation. All SCFA except acetate stimulated distal colon Na+ absorption 200%. Only one SCFA affected proximal colon cGMP phosphodiesterase (PDE) (18% inhibition by 50 mM butyrate). All SCFA at 50 mM stimulated distal colon cAMP PDE (24-43%) and decreased forskolin-stimulated mucosal cAMP content. None of the SCFA affected forskolin-stimulated adenylyl cyclase in distal colon or ST(a)-stimulated guanylyl cyclase in proximal colon. Na+-K+-ATPase in distal colon was inhibited 23-51% by the SCFA at 50 mM. We conclude that all SCFA (except acetate in distal colon) stimulate colonic Na+ absorption equally, and the mechanism does not involve mucosal SCFA metabolism or carbonic anhydrase. SCFA inhibition of cAMP-mediated secretion may involve SCFA stimulation of PDE and inhibition of Na+-K+-ATPase.
Comp Biochem Physiol A Mol Integr Physiol 2001 Feb
PMID:Effects of short chain fatty acids on colonic Na+ absorption and enzyme activity. 1122 95

In addition to metabolic CO2 production and gill ventilatory flow rate, expired water PCO2 is very dependent on water acid-base balance in a complex way. This is particularly true in carbonated waters at low ambient PCO2 and high pH, where CO2 excreted in the gill water may be buffered by carbonate ions, leading to an increased CO2 capacitance coefficient. The higher the carbonate alkalinity (CA) and the lower the inspired PCO2 (i.e., the higher the inspired water pH), the stronger the carbonate buffering and the smaller the increase of PCO2 in the gill water during respiratory CO2 exchanges. As a consequence, as shown by a number of reported data, increasing the CA leads to blood hypocapnia and respiratory alkalosis at constant low, but not at high, inspired PCO2. In the low range of inspired PCO2, internal PCO2 becomes very sensitive to even small changes of water PCO2, which may explain at least in part the large variability of reported blood PCO2 values in gill breathers. Water CA also influences the amplitude of respiratory acid-base disturbances caused by changes of the gill ventilatory flow rate. Carbonate buffering of excreted CO2 and thus dependence of blood PCO2 on water alkalinity requires catalysis of CO2 hydration by carbonic anhydrase, that must be available from the water side of the gill epithelium.
Comp Biochem Physiol A Mol Integr Physiol 1998 Jan
PMID:Effect of water alkalinity on gill CO2 exchange and internal PCO2 in aquatic animals. 1125 77

The disequilibrium pH is defined as any discrepancy between the measured pH and the pH which would exist if CO2-HCO3-H+ reactions were at equilibrium. Measurement of the disequilibrium pH can be used to assess the status of CO2-HCO3--H+ reactions and, in combination with carbonic anhydrase (CA) or CA inhibitor treatments, may also be used to localize CA. Renal physiologists have used disequilibrium experiments to determine that HCO3- reabsorption in the kidney tubule occurs via proton secretion, and that CA activity is available to ultrafiltrate CO2-HCO3-H+ reactions in the proximal convoluted tubule, but not the distal tubule. Disequilibrium experiments were also used in investigating the availability of CA to CO2-HCO3--H+ reactions in water at the fish gill; the opposing results obtained in two studies have not yet been resolved. Respiratory physiologists have used the disequilibrium technique in vivo and with saline-perfused preparations to assess the availability of CA to plasma CO2-HCO3--H+ reactions following gas exchange. Saline-perfused preparations enable direct localization of CA activity, while in vivo measurements encompass the numerous factors affecting CO2-HCO3--H+ equilibration in a multi-phase solution. Given the many organs in which membrane-bound CA activity has now been identified, the usefulness of the disequilibrium pH technique has increased beyond its original applications in renal and pulmonary physiology.
Comp Biochem Physiol A Mol Integr Physiol 1998 Jan
PMID:The disequilibrium pH: a tool for the localization of carbonic anhydrase. 1125 90

Carbonic anhydrase and proton ATPase are co-distributed, being restricted to the apical regions of the gill epithelium of freshwater teleosts. Carbonic anhydrase supplies protons to the apical proton ATPase. Carbonic anhydrase is absent from the basal regions of the gill epithelium. Plasma flowing through the gills has no available carbonic anhydrase activity and plasma CO2/bicarbonate reactions are uncatalyzed. Thus, bicarbonate dehydration in plasma is negligible, and catalyzed bicarbonate dehydration occurs in erythrocytes in blood flowing through the gills. This results in tight coupling of carbon dioxide excretion to oxygen uptake and the evolution of hemoglobins with large Haldane effects but low buffering capacities, typical of many freshwater teleosts. Tight coupling of carbon dioxide and oxygen transfer in these fish also ensures that the Root shift does not impair oxygen uptake at the gills. Under these conditions, there is a selective advantage for hemoglobins with a Root shift. The presence of a Root shift augments oxygen transfer to the tissues in general and the eye and swimbladder in particular.
Comp Biochem Physiol A Mol Integr Physiol 1998 Jan
PMID:Interactions between ion and gas transfer in freshwater teleost fish. 1125 98

The structure and function of the pseudobranch has long interested scientists, but its overall role has remained a mystery. Previous studies have attributed respiratory, endocrine, osmoregulatory and sensory roles to the pseudobranch, and the present review concentrates on new findings. Perfusion experiments on the pseudobranch of the rainbow trout (Oncorhynchus mykiss) using both erythrocyte suspensions and Ringer solution have shown that this organ is able to generate values for the respiratory quotient (RQ) greater than 1.0. The release of carbon dioxide into the perfusate was found to be largely independent of flow between perfusion rates of 120-190 microl/min and could be inhibited by acetazolamide (10(-5) M), indicating a role for carbonic anhydrase. Noradrenaline (10(-5) M) had no effect on oxygen consumption or carbon dioxide release of the pseudobranch. The rate of carbon dioxide release was also dependent on the pH of the pre-pseudobranch perfusate, carbon dioxide release being reduced at lower perfusate pH values. Based on the glucose balance of the isolated saline-perfused rainbow trout pseudobranch and on the enzyme profiles for the rainbow trout, cod, swordfish and deep-water grenadier pseudobranch, it is suggested that the pentose phosphate shunt might be a source of carbon dioxide, yielding the high RQ values found for this organ. Most evidence now available indicates that the pseudobranch is integrally linked with the choroid rete and the supply of oxygen to the retina of the fish eye.
Comp Biochem Physiol A Mol Integr Physiol 1998 Jan
PMID:Physiology and biochemistry of the pseudobranch: an unanswered question? 1125 20


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