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S Svensson

Publications and source records attributed to S Svensson.

At least 19 recordsLinked to original sources
PubMed2000

Crystal structures of mouse class II alcohol dehydrogenase reveal determinants of substrate specificity and catalytic efficiency.

The structure of mouse class II alcohol dehydrogenase (ADH2) has been determined in a binary complex with the coenzyme NADH and in a ternary complex with both NADH and the inhibitor N-cyclohexylformamide to 2.2 A and 2.1 A resolution, respectively. The ADH2 dimer is asymmetric in the crystal with different orientations of the catalytic domains relative to the coenzyme-binding domains in the two subunits, resulting in a slightly different closure of the active-site cleft. Both conformations are about half way between the open apo structure and the closed holo structure of horse ADH1, thus resembling that of ADH3. The semi-open conformation and structural differences around the active-site cleft contribute to a substantially different substrate-binding pocket architecture as compared to other classes of alcohol dehydrogenase, and provide the structural basis for recognition and selectivity of alcohols and quinones. The active-site cleft is more voluminous than that of ADH1 but not as open and funnel-shaped as that of ADH3. The loop with residues 296-301 from the coenzyme-binding domain is short, thus opening up the pocket towards the coenzyme. On the opposite side, the loop with residues 114-121 stretches out over the inter-domain cleft. A cavity is formed below this loop and adds an appendix to the substrate-binding pocket. Asp301 is positioned at the entrance of the pocket and may control the binding of omega-hydroxy fatty acids, which act as inhibitors rather than substrates. Mouse ADH2 is known as an inefficient ADH with a slow hydrogen-transfer step. By replacing Pro47 with His, the alcohol dehydrogenase activity is restored. Here, the structure of this P47H mutant was determined in complex with NADH to 2.5 A resolution. His47 is suitably positioned to act as a catalytic base in the deprotonation of the substrate. Moreover, in the more closed subunit, the coenzyme is allowed a position closer to the catalytic zinc. This is consistent with hydrogen transfer from an alcoholate intermediate where the Pro/His replacement focuses on the function of the enzyme.

Alcohol Dehydrogenase↗
PubMed2000

Cyclic expression of class I alcohol dehydrogenase in male rats treated with ethanol.

Continuous infusion of ethanol-containing diets has been demonstrated to generate well-defined pulses in blood and urine ethanol concentrations that occur with a frequency of approximately 6 days. The present study aimed to determine if hepatic class I alcohol dehydrogenase was the cause of these cycles. Adult male rats were fed an ethanol-containing diet by continuous intragastric infusion. Hepatic ADH activity, class I ADH mRNA level and rate of class I ADH gene transcription fluctuated in a cyclic pattern that positively correlated with UECs, and inhibition of ADH with 4-methylpyrazole abolished the UEC pulses. These data demonstrate for the first time an ethanol-dependent regulation of rat hepatic class I ADH. The cyclic behavior of the ethanol levels correlates with changes in class I ADH expression and implies adaptability of the ethanol eliminating system to high concentrations of alcohol.

Alcohol Dehydrogenase↗
PubMed2000

Studies on the interaction between ethanol and serotonin metabolism in rat, using deuterated ethanol and 4-methylpyrazole.

The metabolic interaction between ethanol and serotonin (5-hydroxytryptamine) via alcohol dehydrogenase (ADH; EC 1.1.1.1) was studied in tissue homogenates of Sprague-Dawley rats by following the transfer of deuterium from deuterated ethanol over endogenous NADH to 5-hydroxytryptophol (5HTOL). Homogenates of whole brain, lung, spleen, kidney, liver, stomach, jejunum, ileum, colon, and caecum were incubated in the presence of [2H2]ethanol and 5-hydroxyindole-3-acetaldehyde (5HIAL), and the [2H]5HTOL formed was identified and quantified using gas chromatography-mass spectrometry. ADH activity was most abundant in liver, kidney, and within the gastrointestinal tract. The highest incorporation of deuterium was obtained in homogenates of kidney, lung, and colon, whereas in brain, which contains very low ADH activity, no incorporation could be demonstrated. Addition of extra NAD+ (2.4 mM) increased the formation of [2H]5HTOL 2.6-fold in liver homogenates, but only 1.2-fold in kidney homogenates. 4-Methylpyrazole, a potent inhibitor of class I ADH, inhibited the 5HIAL reduction in homogenates of lung, kidney, jejunum, ileum, and colon, and caused a marked drop in 5HTOL oxidation in all tissues except stomach and spleen. These results demonstrate that in the rat a metabolic interaction between ethanol and serotonin via the ADH pathway may take place in several tissues besides the liver, which is the main tissue for ethanol detoxification.

Alcohol Dehydrogenase↗
PubMed2000

Antihypertensive treatment and patient autonomy--the follow-up appointment as a resource for care.

Since hypertension is a chronic condition which generally requires long-term commitment to pharmacological therapy as well as alterations of patient lifestyle, the patient-physician communication in the clinical setting is an important determinant of the quality of care and health outcome. The aim of the present study was to explore the structure and content of the communication between the patient and the physician, and the process of decision-making at a routine follow-up appointment for hypertension. The study was based on 51 audio-recordings of authentic consultations. Most patients had a passive role in the consultations, and initiated few topics of conversation. The few topics that the patients initiated were usually not about hypertension. Patients' questions about medication mainly referred to unwanted effects of the drugs. Little time was invested in discussing risks related to hypertension. A collaborative shared decision-making was seldom observed in the consultations.

Adult↗
PubMed2000

Renal effects of amino acid infusion in cardiac surgery.

OBJECTIVE: To evaluate effects of amino acids on renal function and oxygen consumption and the role of individual amino acids on renal blood flow (RBF) changes. DESIGN: Prospective, randomized, controlled study. SETTING: Operating room in cardiothoracic surgery department, university hospital. PARTICIPANTS: Twenty-two male patients submitted to elective first-time coronary artery bypass surgery. INTERVENTIONS: A catheter was placed in the left renal vein for thermodilution RBF measurements and blood sampling. In 11 patients, a balanced mixed amino acid infusion was infused (200 mL/hr) for 30 minutes immediately after the operation. MEASUREMENTS AND MAIN RESULTS: RBF and glomerular filtration rate increased during amino acid infusion compared with the control group. Renal oxygen consumption increased in the amino acid group and correlated with the increase in RBF (r = 0.70, p<0.001). Amino acid infusion induced two- to fourfold increases in plasma concentrations of individual amino acid concentrations and promoted renal extraction of aspartate, glutamate, glycine, and histidine. No correlation was observed between arterial concentration or uptake of individual amino acids and RBF. CONCLUSIONS: The increase in RBF from a mixed amino acid infusion was associated with increased glomerular filtration rate and renal consumption of oxygen. Changes in RBF of a mixed amino acid infusion could not be linked to plasma level or renal uptake of any individual amino acids.

Adult↗
PubMed2000

Human liver class I alcohol dehydrogenase gammagamma isozyme: the sole cytosolic 3beta-hydroxysteroid dehydrogenase of iso bile acids.

3beta-Hydroxy (iso) bile acids are formed during enterohepatic circulation from 3alpha-hydroxy bile acids and constitute normal compounds in plasma but are virtually absent in bile. Isoursodeoxycholic acid (isoUDCA) is a major metabolite of UDCA. In a recent study it was found that after administration of isoUDCA, UDCA became the major acid in bile. Thus, epimerization of the 3beta-hydroxy to a 3alpha-hydroxy group, catalyzed by 3beta-hydroxysteroid dehydrogenases (HSD) and 3-oxo-reductases must occur. The present study aims to characterize the human liver bile acid 3beta-HSD. Human liver cytosol and recombinant alcohol dehydrogenase (ADH) betabeta and gammagamma isozymes were subjected to native polyacrylamide gel electrophoresis (PAGE) and isoelectric focusing. Activity staining with oxidized nicotinamide adenine dinucleotide (NAD(+)) or oxidized nicotinamide adenine dinucleotide phosphate (NADP(+)) as cofactors and various iso bile acids as substrates was used to screen for 3beta-HSD activity. Reaction products were identified and quantified by gas chromotography/mass spectrometry (GC/MS). Computer-assisted substrate docking of isoUDCA to the active site of a 3-dimensional model of human class I gammagamma ADH was performed. ADH gammagamma isozyme was identified as the iso bile acid 3beta-HSD present in human liver cytosol, with NAD(+) as a cofactor. Values for k(cat)/K(m) were in the rank order isodeoxycholic acid (isoDCA), isochenodeoxycholic acid (isoCDCA), isoUDCA, and isolithocholic acid (isoLCA) (0.10, 0.09, 0.08, and 0. 05 min(-1) x micromol/L(-1), respectively). IsoUDCA fits as substrate to the 3-dimensional model of the active-site of ADH gammagamma. ADH gammagamma isozyme was defined as the only bile acid 3beta-HSD in human liver cytosol. Hydroxysteroid dehydrogenases are candidates for the binding and transport of 3alpha-hydroxy bile acids. We assume that ADH gammagamma isozyme is involved in cytosolic bile acid binding and transport processes as well.

3-Hydroxysteroid Dehydrogenases↗
PubMed2000

Body mass index as a predictor of 1 year mortality in geriatric patients.

BACKGROUND AND AIMS: The predictive value of body mass and functional capacity for 1 year mortality was examined retrospectively in 552 consecutive geriatric patients categorized in 14 diagnosis groups. METHODS: Data on body mass index (BMI, kg/m(2)) was retrievable from 337 subjects. In 532 patients, Katz indexes of activities of daily life (ADL, A-G; A=independent, G total dependence) were registered. The mean age (+/- SD) was 81 +/- 8 years, two-thirds were women and 75% lived alone. Mortality data was obtained from the Swedish population records. RESULTS: Thirty-six per cent of the patients had BMI values < or =43% had BMI 21-25 and 21% > 25. Less than 2% were diagnosed as malnourished. The 1 year mortalities of those with BMI < or = 20, BMI 21-25 and BMI > 25 were 48%, 29% and 18% respectively (P< 0.001). Katz ADL index was significantly worse in those with BMI > 20 as compared with those having BMI < or = 20 (Katz D and C (P< 0.01) respectively). Patients with chronic obstructive lung disease displayed the lowest BMI values, i.e. 20 +/- 4. A logistic regression analysis indicated that BMI, gender and Katz ADL index, but not age, diagnosis or marital status, were independent predictors of 1 year mortality. CONCLUSION: Depletion may still be an overlooked problem in geriatric patients, in whom low body mass index appears to be independently associated with imminent death.

Activities of Daily Living↗
PubMed1999

A novel subtype of class II alcohol dehydrogenase in rodents. Unique Pro(47) and Ser(182) modulates hydride transfer in the mouse enzyme.

Mice and rats were found to possess class II alcohol dehydrogenases with novel enzymatic and structural properties. A cDNA was isolated from mouse liver and the encoded alcohol dehydrogenase showed high identity (93.1%) with the rat class II alcohol dehydrogenase which stands in contrast to the pronounced overall variability of the class II line. The two heterologously expressed rodent class II enzymes exhibited over 100-fold lower catalytic efficiency (k(cat)/K(m)) for oxidation of alcohols as compared with other alcohol dehydrogenases and were not saturated with ethanol. Hydride transfer limited the rate of octanol oxidation as indicated by a deuterium isotope effect of 4.8. The mutation P47H improved hydride transfer and turnover rates were increased to the same level as for the human class II enzyme. Michaelis constants for alcohols and aldehydes were decreased while they were increased for the coenzyme. The rodent class II enzymes catalyzed reduction of p-benzoquinone with about the same maximal turnover as for the human form. This activity was not affected by the P47H mutation while a S182T mutation increased the K(m) value for benzoquinone 10-fold. omega-Hydroxy fatty acids were catalyzed extremely slow but functioned as potent inhibitors by binding to the enzyme-NAD(+) complex. All these data indicate that the mammalian class II alcohol dehydrogenase line is divided into two structurally and functionally distinct subgroups.

Alcohol Dehydrogenase↗
PubMed1999

Activities of human alcohol dehydrogenases in the metabolic pathways of ethanol and serotonin.

Alcohols and aldehydes in the metabolic pathways of ethanol and serotonin are substrates for alcohol dehydrogenases (ADH) of class I and II. In addition to the reversible alcohol oxidation/aldehyde reduction, these enzymes catalyse aldehyde oxidation. Class-I gammagamma ADH catalyses the dismutation of both acetaldehyde and 5-hydroxyindole-3-acetaldehyde (5-HIAL) into their corresponding alcohols and carboxylic acids. The turnover of acetaldehyde dismutation is high (kcat = 180 min-1) but saturation is reached first at high concentrations (Km = 30 mm) while dismutation of 5-HIAL is saturated at lower concentrations and is thereby more efficient (Km = 150 microm; kcat = 40 min-1). In a system where NAD+ is regenerated, the oxidation of 5-hydroxytryptophol to 5-hydroxyindole-3-acetic acid proceeds with concentration levels of the intermediary 5-HIAL expected for a two-step oxidation. Butanal and 5-HIAL oxidation is also observed for class-I ADH in the presence of NADH. The class-II enzyme is less efficient in aldehyde oxidation, and the ethanol-oxidation activity of this enzyme is competitively inhibited by acetate (Ki = 12 mm) and 5-hydroxyindole-3-acetic acid (Ki = 2 mm). Reduction of 5-HIAL is efficiently catalysed by class-I gammagamma ADH (kcat = 400 min-1; Km = 33 microm) in the presence of NADH. This indicates that the increased 5-hydroxytryptophol/5-hydroxyindole-3-acetic acid ratio observed after ethanol intake may be due to the increased NADH/NAD+ ratio on the class-I ADH.

Alcohol Dehydrogenase↗
PubMed1999

The physiological basis for faster growth in the Sydney rock oyster, Saccostrea commercialis

Sydney rock oysters were sampled from a mass selection experiment for growth (the "selected" category) and from a control ("not selected") population and held in the laboratory at three ration levels. We evaluated three models to explain faster rates of growth by selected oysters. Selection resulted in oysters feeding at up to twice the rate and with greater metabolic efficiency than controls. A field experiment confirmed that selection leads to faster rates of feeding across a wide range of food concentrations. Selected oysters also grew more efficiently, at a smaller cost of growth (Cg): mean values for Cg were 0.43 J x J(-1) in selected individuals and 0.81 J x J(-1) in the controls. In contrast, oysters in both categories showed similar metabolic rates at maintenance, i.e., at a ration supporting zero growth. There was no evidence that differential energy allocation affected the balance between total metabolic requirements above and below zero net energy balance. By experimenting with selected and control oysters of different sizes and ages, then standardizing the data for size, we found no effects of age on the differences due to selection. Faster-growing oysters feed more rapidly; invest more energy per joule ingested; show a higher net growth efficiency; and are able to allocate less energy per unit of tissue growth, than slower-growing individuals.

Journal Article↗
PubMed1998

Biosensing with G-protein coupled receptor systems.

Many cell membrane bound receptors communicate with the inside of the cell through guanine nucleotide binding proteins (G-proteins). This holds also for olfactory receptor neurons, which respond to odorants with G-protein mediated increases in the concentration of cyclic adenosine 3', 5'-monophosphate (cAMP) and/or inositol 1,4,5-triphosphate (InsP3). These substances regulate the ionic conductivity of the wall of the cilia. We have studied a similar system, namely G-protein coupled alpha 2-adrenoceptors, present for example in the cells of certain fish scales. These receptors react on, catecholamines and the G-protein mediates a decrease in cAMP, which causes an aggregation of pigment containing granulas to the middle of the cells. The light transmission of the cell increases due to this aggregation. This simple physiological response has been used in a sensitive biosensor for noradrenaline and for pertussis toxin that is based on isolated fish scales from cuckoo wrasse (Labrus ossifagus). The results were obtained with a simple photometer. Measurements can be performed also on single isolated melanophores. The main purpose of this contribution is, however, to point out that G-protein coupled receptors together with a simple physiological response form a principle for biosensing, which could also be an interesting alternative for odour sensing.

Animals↗
PubMed1998

Antihypertensive medication in clinical encounters.

In managing hypertension, patient participation and understanding of the nature and significance of treatment are decisive. We analysed the communication between patient and physician with respect to antihypertensive medication at a follow-up appointment, and assessed patients' knowledge of their medication. The empirical data consist of audio-recordings from 51 hypertensive patients' follow-up appointment with their physicians. Thirty-three of these patients were interviewed in depth immediately after the appointment. The study was performed in primary health care centres and at a specialist clinic for hypertension. When discussing medications, patients mainly talked about experiences of being on medication, whereas physicians generally focused on the pharmacological effect and dosage of the drug. Physicians routinely asked about compliance with drug regimen, but seldom in any depth. Little effort was invested into discussing the effect and goal of therapy. The main finding was that patients had a very fragmentary understanding of the functional nature of their antihypertensive medication. This is unsatisfactory both from the point of view of treatment efficacy and also when considering the legal requirements of involving the patient in the decision making. The follow-up appointments studied gave few possibilities for the patient to learn about their antihypertensive medication.

Aged↗
PubMed1998

Structural and functional divergence of class II alcohol dehydrogenase--cloning and characterisation of rabbit liver isoforms of the enzyme.

cDNAs coding for class II alcohol dehydrogenase were isolated from a rabbit-liver cDNA library. Deduced amino acid sequences show that isozymic forms of rabbit class II alcohol dehydrogenase exist, with a positional identity of 88.4%. A high variability in structure of class II alcohol dehydrogenase between the species is also reflected in function. The rabbit II-1 isozyme shows common characteristics with the human enzyme, but has a lower Km value for ethanol, 4.2 mM. The II-2 isozyme shows restriction for aliphatic alcohols longer than pentanol. For shorter alcohols the II-2 form has similar Km values as the II-1 isozyme, 5.5 mM for ethanol, but is a low activity variant with a 10-fold decrease in k(cat) values compared with II-1. Nevertheless, II-2 has a higher specificity for benzoquinone than II-1 due to a lower Km value, 80 microM compared with 1 mM, and is in this sense more like the human class II enzyme. In addition a rabbit class III alcohol dehydrogenase cDNA was isolated that encodes a typical class III enzyme/glutathione-dependent formaldehyde dehydrogenase. The finding of isozymic forms of class II alcohol dehydrogenase is in line with the evolution of the system of medium-chain alcohol dehydrogenases with different enzymes, different classes and different isozymes and further underline the complexity of the entire mammalian alcohol dehydrogenase system.

Alcohol Dehydrogenase↗
PubMed1998

Renal effects of alpha-ketoglutarate early after coronary operations.

BACKGROUND: Alpha-ketoglutarate (alpha-KG) is a Krebs cycle intermediate and the carbon skeleton of glutamate. Alpha-ketoglutarate has provoked interest in heart surgery because of its proposed critical role in myocardial metabolism. This study investigates the role of alpha-KG in renal function after cardiac surgical procedures. METHODS: Twenty-two patients with normal preoperative renal function were included in a prospective, randomized, and controlled study. Eleven patients received intravenous infusion of 30 g alpha-KG/hour after the operation. Measurements were performed before operation, immediately after operation, and after 30 minutes of alpha-KG infusion. RESULTS: Renal blood flow was higher during alpha-KG infusion, 297% +/- 97% (of preoperative value), than in controls, 125% +/- 20% (p < 0.05). Filtration fraction was lower (12.3% +/- 0.05% versus 17.2% +/- 1.1%, p < 0.01), which prevented a significant difference in glomerular filtration rate. The renal arteriovenous differences of lactate, glutamate, glutamine, and glycine changed toward a net release during alpha-KG infusion. CONCLUSIONS: Infusion of alpha-KG enhances renal blood flow early after coronary surgical procedures in patients with normal renal function. The mechanism is unclear, but could be associated with primarily metabolic effects, and may potentially convey a beneficial effect for renal function.

Adult↗