Flavinylation of succinate: ubiquinone oxidoreductase from Saccharomyces cerevisiae.
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Cell Fractionation↗
Biomedical subjects
K M Robinson
Publications and source records attributed to K M Robinson.
The relationship between health and social support in caregiving wives as perceived by significant others.
This study explored the relationship between health and social support in wives who care for husbands with dementia. In order to understand how significant others begin mobilizing help for caregivers, the significant others' views of the carers' health and social support were analysed. Subjects comprised 75 significant others identified as being familiar with the caregiving situation of a like number of caregiving wives. Hypotheses, which were rejected, predicted that wife caregivers perceived as ill by the significant other would be seen as needing and receiving more social support as reported by the significant other. Findings indicated that healthy caregivers were perceived to have significantly more people in their social network.
Adult↗
Sentence comprehension in multiple sclerosis.
INTRODUCTION: Explanations of sentence processing difficulty in aphasia have implicated slowed information processing speed. We tested this hypothesis by evaluating sentence comprehension in multiple sclerosis (MS), and relating comprehension performance to measures of information processing speed. MATERIAL & METHODS: Twenty right-handed, high school-educated, non-demented, native English speakers with clinically definite MS and 16 age- and education-matched control subjects were examined on 3 different sentence comprehension measures that stress grammatical appreciation. Performance was related to quantitative assessments of mental information processing speed. RESULTS: Group-wide analyses demonstrated a trend toward sentence comprehension difficulty in MS. Analyses of individual patient profiles identified a subgroup of MS patients who were consistently impaired to a significant extent across all sentence comprehension tasks. Their sentence comprehension difficulty was associated with selectively compromised mental information processing speed. CONCLUSION: Sentence comprehension difficulty in MS is associated with slowed information processing speed. This finding supports the claim that information processing speed contributes to sentence processing.
Adult↗
Phonologic processing deficits in Alzheimer's disease.
We investigated phonologic production in patients with mild to moderate Alzheimer's disease (AD) on a repetition task. AD patients produced significantly more speech errors than age-matched controls. AD patients' errors, unlike those of controls, resulted in the transformation of real words into pseudowords, occurred disproportionately in word-initial positions, and were not influenced by the phonologic environment. This pattern of errors suggests a lexical phonologic retrieval deficit in AD.
Aged↗
The covalent attachment of FAD to the flavoprotein of Saccharomyces cerevisiae succinate dehydrogenase is not necessary for import and assembly into mitochondria.
Succinate dehydrogenase of the bacterial or inner mitochondrial membrane catalyses the oxidation of succinate to fumarate and directs reducing equivalents into the electron-transport chain. The enzyme is also able to catalyse the reverse reaction, the reduction of fumarate to succinate. The enzyme is composed of four subunits. These subunits include a catalytic dimer composed of a flavoprotein subunit with a covalently bound FAD, and an iron-sulfur protein subunit with three different iron-sulfur centres, which is anchored to the membrane by two smaller integral membrane proteins. The FAD moiety is attached to the flavoprotein subunit by an 8 alpha-[N(3)-histidyl]FAD linkage at a conserved histidine residue, His90 of the Saccharomyces cerevisiae succinate dehydrogenase. By mutating His90 to a serine residue, we have constructed a flavoprotein subunit that is unable to covalently bind FAD. The mutant flavoprotein is targeted to mitochondria, translocated across the mitochondrial membranes, and is assembled with the other subunits where it binds FAD non-covalently. The resulting holoenzyme has no succinate-dehydrogenase activity but retains fumarate reductase activity. The covalent attachment of FAD is therefore necessary for succinate oxidation but is dispensable for both fumarate reduction and for the import and assembly of the flavoprotein subunit.
Binding Sites↗
MDL 29311, an analog of probucol, decreases triglycerides in rats by increasing hepatic clearance of very-low-density lipoprotein.
MDL 29311 is an analog of probucol that shares probucol's antioxidant and antiatherogenic properties. When fed to rats as a 1% dietary admixture, MDL 29311 decreased triglyceride levels by 65% without affecting total or high-density lipoprotein (HDL) cholesterol levels. Under the same conditions, probucol decreased triglyceride levels by 23% and total cholesterol levels by 29% (with a corresponding decrease in HDL cholesterol level). MDL 29311 treatment did not affect the rate of triglyceride entry into the plasma. However, MDL 29311-treated rats cleared in vivo-labeled very-low-density lipoprotein (VLDL)-associated [3H]-triglyceride ([3H]-VLDL) over threefold faster than control rats. This increase in clearance led to increased levels of [3H]-lipid in liver and decreased [3H]-lipid in fat, muscle, diaphragm, and kidney of MDL 29311-treated rats 1.5 to 2.0 minutes after injection of [3H]-VLDL. MDL 29311 treatment had no effect on lipoprotein lipase (LPL) or hepatic triglyceride lipase (H-TGL) activities, or on plasma apolipoprotein (apo) C-II-dependent LPL activation. Intravenously injected [3H]-VLDL was allowed to circulate in MDL 29311-treated or control rats for 1 minute, and the undiluted plasma was then perfused through rat livers in a recirculating system. The [3H] in MDL 29311 plasma was cleared threefold faster (t1/2, 1.3 v 3.8 minutes) than the [3H] in control plasma by control livers. Conversely, the [3H] in control plasma was cleared slowly (t1/2 = 3.5 minutes) by the livers of MDL 29311-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Spirituality among caregivers.
The spiritual perspectives of 17 caregiver wives of dementia victims and 23 noncaregiving wives of healthy adults were compared in a pilot study using a convenience sample. Caregiver wives used symbols such as God, and spiritual behaviors such as prayer and forgiveness as coping mechanisms. Caregivers tended to share the problems and joys of living according to their spiritual belief more often than the noncaregiver wives of healthy adults. Caregivers also engaged in private prayer and sought spiritual guidance in making decisions in their everyday life more often. The findings suggest that nursing interventions with churches as a natural network for caregivers may be useful. Prayer, forgiveness, and spiritual reading materials are resources that may be helpful to some caregivers.
Adaptation, Psychological↗
The relationship between spiritual perspective, social support, and depression in caregiving and noncaregiving wives.
The purpose of this study was to compare the relationships between spiritual perspective, social support, and depression in two groups of adults: caregiving wives of dementia victims and noncaregiving wives of healthy adults. Hypotheses predicted that increased spiritual perspective would be associated with increased social support and decreased depression in caregiving wives. Hypotheses also predicted that spiritual perspective would be more strongly associated with these variables in caregiving wives. Spiritual perspective was not significantly related to social support or depression in the caregivers. The relationships between these variables, however, were noted to be stronger in caregiving wives than in noncaregivers. Employment and increased availability of support were associated with decreased depression in caregivers.
Aged↗
Geriatrics training in physical medicine and rehabilitation.
A survey was conducted to determine the level of training in geriatrics in physical medicine and rehabilitation (PM&R) residency training programs. Questionnaires were sent to 76 accredited programs in 1989 with a 63% (48/76) response rate. Results show that 49% of patients cared for by PM&R residents in inpatient settings are 65 years of age or older, and 42% of patients cared for in ambulatory settings are in the same age group. Of PM&R programs, 30% have physician faculty who are geriatric "specialists." PM&R residents have a significant exposure to elderly patients in the consultation role. Less exposure to elderly patients occurs in distinct geriatric rehabilitation and geriatric medicine programs or units. Among 10 medical specialties, PM&R programs compare well in terms of teaching about the topics and the personnel that are important in geriatrics. This is due in part to an obvious overlap between the content of rehabilitation medicine and that of geriatrics. Furthermore, there is moderate interest in PM&R in developing fellowship training in geriatric rehabilitation. The need for more academic faculty who are geriatric "specialists," as well as the need for increasing PM&R exposure to distinctly geriatric settings as a part of training, is apparent.
Education, Medical↗
Antioxidant MDL 29,311 prevents diabetes in nonobese diabetic and multiple low-dose STZ-injected mice.
Recent investigations suggest a role for antioxidants in preventing IDDM. MDL 29,311 (4,4'-[methylenebis(thio)]bis](1,1- dimethylethyl)]-phenol) is an analogue of the antioxidant probucol. Administered as a 1% dietary admixture to female nonobese diabetic mice from 4 to 24 wk of age, MDL reduced the prevalence of diabetes from 49 to 4% at 24 wk of age (n = 50-61/group). Discontinuation of treatment at 24 wk of age did not result in a rapid onset of diabetes. Probucol (1%) did not prevent diabetes. Initiating MDL treatment at 4 or 8 wk of age was more effective (19 and 17%, respectively, compared with 60% in control mice) than initiating treatment at 12 wk of age (30% diabetic; n = 28-35/group). A lower dose of MDL (0.1%), started at 4 wk of age, decreased the prevalence of diabetes to 36%. Histopathology indicated that MDL did not prevent insulitis. MDL (0.1%) also was evaluated in combination with immunosuppressants. Compared with control mice (65% diabetic), the combination of MDL and deflazacort was more effective (21% diabetic) than either agent alone (39% diabetic for MDL and 59% diabetic for deflazacort), whereas the effectiveness of MDL, cyclosporin, and MDL plus cyclosporin was similar (39, 38, and 34% diabetic, respectively). In another model of IDDM, the multiple-low-dose streptozocin-injected mouse, MDL (1%) also reduced the prevalence of diabetes when administered beginning 8 wk before streptozocin (55% diabetic vs. 100% of control mice; n = 20-25/group). Probucol (1%) was ineffective. MDL appears effective in preventing the onset of disease in two mouse models of IDDM.
Aging↗
MDL 29311. Antioxidant with marked lipid- and glucose-lowering activity in diabetic rats and mice.
MDL 29311, an analogue of probucol, administered to rats as a 1% dietary admixture for 2 wk before and 5 days after intravenous injection of 40 mg/kg of ALX significantly (P < 0.05) reduced plasma glucose (6.9 +/- 0.3 vs. 19.2 +/- 1.3 mM) and serum triglyceride (0.17 +/- 0.01 vs. 1.82 +/- 0.39 mM) levels in overnight-fasted ALX-plus-MDL 29311-administered rats vs. ALX-administered rats. A cross-over study indicated that MDL 29311 did not attenuate the diabetogenic action of ALX, but rather, directly lowered glucose and triglycerides. In rats injected intravenously with 45, 65, or 85 mg/kg of STZ and then administered control or MDL 29311 diet for 7 days, MDL 29311 decreased fasted plasma glucose to nondiabetic levels, decreased fasted and nonfasted plasma triglycerides by 49-79%, but did not affect plasma insulin levels. In STZ-induced (65 mg/kg) diabetic rats, MDL 29311 attenuated the increase in plasma nonesterified fatty acids during an 18-h fast; had little or no effect on glucagon, pyruvate, lactate, beta-hydroxybutyrate, acetoacetate, or cholesterol; and did not induce hypoglycemia in rats fasted up to 64 h. In nonfasted hyperinsulinemic db/db mice treated for 10 wk, MDL 29311 significantly lowered glucose levels by 14-40%, triglyceride levels by 31-63% and GHb from 8.0 to 5.4%, and had no consistent effect on plasma insulin levels. Because of its marked glucose- and lipid-lowering activity in both nonfasted hyperinsulinemic and fasted insulinopenic animals, MDL 29311 merits additional investigation as a potential antidiabetic agent.
Animals↗
Isolation and nucleotide sequence of the Saccharomyces cerevisiae gene for the succinate dehydrogenase flavoprotein subunit.
Succinate dehydrogenase (EC 1.3.99.1) of the mitochondrial inner membrane is a four-subunit membrane-bound enzyme that catalyzes the oxidation of succinate to fumarate and the transfer of electrons into the electron transport chain to oxygen. The catalytic domain of the enzyme is composed of a flavoprotein subunit which contains a covalently attached FAD cofactor and an iron-sulfur subunit with three nonidentical iron-sulfur clusters. We have isolated a complete genomic clone for the flavoprotein subunit of the succinate dehydrogenase from Saccharomyces cerevisiae and determined its nucleotide sequence. The sequence predicts a protein of 70,185 Da (640 amino acids) that shows more similarity to the Escherichia coli succinate dehydrogenase flavoprotein subunit than it does to the only other mitochondrial homologue, the human flavoprotein subunit. The yeast flavoprotein subunit precursor was synthesized in a cell-free translation system and shown to possess a mitochondrial targeting sequence that directs its import into isolated, energized mitochondria where it is processed by the matrix-localized protease. The genes for the flavoprotein and the iron-sulfur subunits reside on different chromosomes and hence form different transcriptional units.
Amino Acid Sequence↗
Isolation and characterization of a Saccharomyces cerevisiae mutant disrupted for the succinate dehydrogenase flavoprotein subunit.
A partial genomic clone of the flavoprotein subunit of the mitochondrial enzyme, succinate dehydrogenase (EC 1.3.99.1) from Saccharomyces cerevisiae has been isolated. The partial clone was used to construct, by targeted gene disruption, a yeast mutant with a defective flavoprotein subunit gene. Submitochondrial membranes from the mutant are defective in activities requiring a functional succinate dehydrogenase but not in other respiratory chain activities. In addition, the mutant contains significantly lower levels of covalently attached flavin adenine dinucleotide cofactor than does the wild type. Disruption of the flavoprotein subunit gene results in the simultaneous loss of both the iron-sulfur and the flavoprotein subunits from mitochondrial membranes.
Amino Acid Sequence↗
Quantitative relationship of lysosomal glycogen accumulation to lysosomal alpha-glucosidase inhibition in castanospermine-treated rats.
To quantitatively examine the relationship between lysosomal acid alpha-glucosidase (LAAG, alpha-D-glucoside glucohydrolase, EC 3.2.1.20) inhibition and glycogen accumulation, rats were treated with castanospermine (CS), and liver lysosomal/mitochondrial fractions were analyzed for glycogen content and LAAG activity. Liver lysosomal glycogen accumulation positively correlated (r = 0.90) with the amount of LAAG inhibition when inhibition was about 50% or greater. Glycogen did not accumulate when LAAG inhibition was less than 50%. The route of CS administration had little effect on the amount of LAAG inhibition observed. In rats killed 17 hr after CS administration, the doses estimated to cause 50% LAAG inhibition were 0.77, 0.11, and 0.22 mg/kg for i.p., i.v., and oral administration respectively. After 89% inhibition of LAAG activity with a single oral dose of 10 mg CS/kg, LAAG activity returned to 50% of normal value in about 2.5 days. Accumulated glycogen disappeared as LAAG activity recovered. Surprisingly, twelve daily CS doses of 1 mg/kg had only a small cumulative effect on LAAG inhibition and did not cause more glycogen accumulation than a single dose.
Alkaloids↗
New potent alpha-glucohydrolase inhibitor MDL 73945 with long duration of action in rats.
Inhibition of intestinal alpha-glucohydrolase activity is one approach for reducing the glycemic response from dietary carbohydrate and may prove useful for the treatment of diabetes mellitus. In this article, we describe the pharmacological properties of a time-dependent intestinal alpha-glucohydrolase inhibitor, MDL 73945. When preincubated 2 h with a rat intestinal mucosa preparation before substrate addition, MDL 73945 was a potent inhibitor of sucrase, maltase, glucoamylase, and isomaltase activities (MDL 73945 concentrations required to cause a 50% decrease in enzyme activity, 2 x 10(-7), 1 x 10(-6), 5 x 10(-6), and 8 x 10(-6) M, respectively); without preincubation, it was 10- to 500-fold less potent. In rats, a single oral dose of MDL 73945 administered simultaneously with 2 g/kg body wt sucrose resulted in a dose-dependent reduction in the area under the 0- to 3-h glycemic response curve, which was significant at 1 (45% reduction) and 3 (65% reduction) mg/kg. When administered 1 h before sucrose, the compound was more potent, with 0.3 mg/kg MDL 73945 significantly reducing the glycemic response to sucrose by 62%. A reduction in the glycemic response to sucrose was accompanied by reduced insulin secretion. MDL 73945 was slightly less effective against a starch load, with 3 and 10 mg/kg MDL 73945 administered 0.5 h before starch reducing the glycemic response by 39 and 52%, respectively. MDL 73945 was more effective against a sucrose load in streptozocin-administered rats than in control rats and was as effective after 16 daily doses as after a single dose.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Alzheimer's disease: the patient.
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Aged↗
Castanospermine-glucosides as selective disaccharidase inhibitors.
Castanospermine (CS) is a potent but non-selective inhibitor of many glycohydrolases including the intestinal disaccharidases. Several CS-glucosides were synthesized to investigate the effect of an attached glucopyranosyl residue on the potency and selectivity of CS toward inhibition of intestinal disaccharidases. 8 alpha-glucosyl-CS and 7 alpha-glucosyl-CS were nearly as potent against sucrase activity as CS (IC50 values = 30, 40, and 20 nM respectively) but were 1/50 or less as potent as CS against lactase and trehalase activities. 8 beta-glucosyl-CS was 1/20 to 1/140 as potent as CS and 1 alpha-glucosyl-CS was 1/57 to 1/1500 as potent as CS against disaccharidase activities. 1 alpha-glc-CS was less selective than CS, whereas the other CS-glucosides were more selective. 7 alpha-glc-CS and 8 alpha-glc-CS were the most sucrase selective and were particularly ineffective against trehalase and lactase activities. 8 beta-glc-CS was similar to CS except for relatively weaker trehalase inhibition. In summary, selectivity toward certain disaccharidases was achieved by glucosylation of CS hydroxyls. However, a simple structural comparison of the CS-glucoside to a disaccharide substrate did not reliably predict which disaccharidase would be more inhibited by the CS-glucoside.
1-Deoxynojirimycin↗
Quantitative relationship between intestinal sucrase inhibition and reduction of the glycemic response to sucrose in rats.
We have investigated the quantitative relationship between sucrase inhibition and reduction in the 0-3 h glycemic response to an oral dose of sucrose in rats. Castanospermine is a quasi-irreversible sucrase inhibitor that did not dissociate from sucrase during tissue preparation or assay for sucrase activity. An oral dose of castanospermine (0.1-3.0 mg/kg body wt) dose-dependently reduced sucrase activity of intestinal segments by 15-90%; 0.4 mg/kg body wt reduced total sucrase activity about 50%. The lower doses inhibited sucrase much more extensively in the proximal than in the distal segments. Castanospermine also dose-dependently reduced the 0-3 h glycemic response to sucrose; 1.5 mg/kg body wt reduced the glycemic response about 50%. Each submaximal castanospermine dose inhibited total sucrase activity more than it reduced the glycemic response. We conclude that intestinal sucrase activity in the rat is in modest excess relative to the rate-determining step of glucose absorption following sucrose administration. Fourteen days of castanospermine treatment (0.2 mg.kg body wt-1.d-1) resulted in sucrase inhibition that was similar to a single castanospermine treatment, suggesting that castanospermine treatment resulted in neither cumulative sucrase inhibition nor induction of sucrase activity.
Alkaloids↗