Cushing's syndrome without excess cortisol.
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Administration, Inhalation↗
Biomedical subjects
D R Woods
Publications and source records attributed to D R Woods.
Angiotensin-converting enzyme genotype and the ventilatory response to exertional hypoxia.
The "insertion" (I) rather than "deletion" (D) variant of the human angiotensin-converting enzyme (ACE) gene is associated with both lower tissue ACE activity and elite performance at high altitude. Three genotypes, II, ID and DD, are thus represented in the population. The authors examined whether an improved ventilatory response to hypoxic exercise may contribute to this effect. Subjects (n=60; 37 male, mean+/-SEM age 23.6+/-0.6 yrs, 14 II, 30 ID, 16 DD) underwent incremental cardiopulmonary exercise testing to establish maximal oxygen uptake and ventilatory threshold (VT). Four hours later, subjects exercised for 6 mins at 50% of the workload at VT. The protocol was repeated 15 mins later while breathing 12.5+/-0.5% oxygen in nitrogen. All subject characteristics were independent of genotype, as were data during normoxic exercise. However, the hypoxia-induced rise in minute ventilation was significantly greater among those of II genotype (39.6+/-4.1% versus 27.9+/-2.0% versus 28.4+/-2.2% for II versus ID versus DD, respectively). These data are supported by a significantly greater decrease in end tidal carbon dioxide (consistent with an increase in alveolar ventilation) among those homozygous for the I allele (II -18.7+/-1.3%, ID -15.7+/-0.4%, DD -15.1%+/-1.1). The ventilatory response to hypoxic exercise is influenced by angiotensin-converting enzyme genotype. Potential implications concern high altitude performance and the pathogenesis and management of hypoxic lung disease.
Adult↗
Endurance enhancement related to the human angiotensin I-converting enzyme I-D polymorphism is not due to differences in the cardiorespiratory response to training.
Human physical performance is strongly influenced by genetic factors. We have previously reported that the I variant of the human angiotensin I-converting enzyme (ACE) gene is associated with greater endurance performance in mountaineers and Olympic runners and improved performance in army recruits. In this study we examined whether this effect is mediated by improvements in cardiovascular fitness with training in 58 army recruits homozygous for the insertion (I, ACE genotype II) or deletion (D, ACE genotype DD) allele. A submaximal and maximal exercise protocol was used to calculate both the heart rate/oxygen uptake (VO2) relationship and changes in maximal oxygen uptake (VO2max), respectively. There was no significant intergroup difference in VO2max at baseline (P=0.19) or after training (P=0.22). There was no difference between genotypes with training in the heart rate/VO2 elevation (P = 0.79 for the mean difference in mean adjusted heart rates). However, VO2 at all exercise intensities in the submaximal test was lower for all subjects after training and at 80 W the reduction in VO2 was greater for the II subjects compared to DD subjects [mean(SEM)] [1.6 (0.27) and 0.68 (0.27) ml kg(-1) min(-1), respectively; P = 0.02 for mean difference]. The I/D polymorphism may play a role in enhanced endurance performance but this is not mediated by differences in VO2max or the heart rate/VO2 relationship in response to training.
Exercise↗
The angiotensin converting enzyme I/D polymorphism in Russian athletes.
The deletion (D) allele of the human ACE gene is associated with higher ACE activity than the insertion (I) allele. There is controversy as to whether the ACE genotype may be associated with elite athletic status; recent studies have identified no significant associations amongst those drawn from mixed sporting disciplines. However, such lack of association may reflect the mixed nature of such cohorts, given that an excess frequency of the I allele has been reported amongst elite endurance athletes, and an excess of the D allele amongst those engaged in more power-orientated sports. We examined this hypothesis by determining ACE I/D allele frequency amongst 217 Russian athletes (swimmers, skiers, triathletes and track-and-field participants) prospectively stratified by performance ('outstanding' or 'average'), and the duration of their event (SDA (<1 min), MDA (1 to 20 min), and LDA (>20 min): short, middle and long distance athletes respectively). ACE genotype and allele frequencies were compared to 449 controls. ACE genotype frequency amongst the whole cohort, or the outstanding athletes alone, was no different to that amongst sedentary controls. However, there was an excess of the D allele (frequency 0.72, P=0.001) amongst the outstanding SDA group, and an excess of the I allele (frequency 0.63, P=0.032) amongst the outstanding MDA group. These findings were replicated in the outstanding swimmers, with track and field SDA similarly demonstrating an excess of the D allele (P=0.01). There was no association found between the outstanding LDA and ACE genotype (P=0.27). These data not only confirm an excess of the D allele in elite SDA, and I allele in elite MDA, but also offer an explanation as to why any such association may be hard to detect amongst a heterogeneous cohort of mixed athletic ability and discipline.
Adult↗
Increased QT dispersion with the D-allele of the ACE polymorphism.
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Alleles↗
Angiotensin-converting enzyme and genetics at high altitude.
As part of the renin-angiotensin system (RAS), angiotensin-converting enzyme (ACE) plays a key role in circulatory homeostasis. ACE degrades vasodilator kinins and generates angiotensin II. A polymorphism in intron 16 of the human ACE gene has been identified in which the presence (insertion, I allele) rather than the absence (deletion, D allele) of a 287 bp fragment is associated with lower serum and tissue ACE activity. The I allele has been associated with some aspects of endurance performance, being found with excess frequency in elite distance runners, rowers, and other elite athletes. Mountaineers also demonstrate an allele skew with a significant excess of the I allele and II genotype in elite, male, British mountaineers who have ascended beyond 7000 m without the use of supplemental oxygen. This review evaluates the evidence for and against an association of the I allele with human endurance, and performance at high altitude. We conclude that the I allele does confer an advantage, most likely mediated via improved muscle efficiency with secondary benefits in terms of conservation of non-fat mass.
Alleles↗
The ACE gene and muscle performance.
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Adult↗
The ACE I/D polymorphism and human physical performance.
The D allele of the angiotensin-converting enzyme (ACE) I/D polymorphism is associated with elevated levels of serum and tissue ACE, increased production of the vasopressor angiotensin II and a reduction in the half-life of the vasodilator bradykinin. Several cardiac and renal conditions appear to have a worse prognosis in subjects homozygous for the D allele, whereas the I allele has been associated with enhanced endurance performance in elite distance runners, rowers and mountaineers. The nature of the gene-environment interaction between ACE I/D polymorphisms and physical training, an overview of recent findings and a discussion of possible underlying mechanisms is the subject of this review.
Humans↗
Endurance and the ACE I/D polymorphism.
A variant of the angiotensin-converting enzyme (ACE) gene, which we all carry, is known as the insertion, or I allele, due to the presence of a 287 base pair DNA fragment. This variant, or polymorphism, is associated with reduced levels of serum and tissue ACE. This intriguing polymorphism has been associated with various physiological and pathological states from diabetic renal disease to coronary heart disease. There have been conflicting reports regarding its association with some aspects of enhanced endurance performance in elite athletes. This review aims to examine the evidence for and against an association of the I allele with endurance and highlight some of the possible mechanism that might be involved. It is concluded that an association seems likely and that it is probably due to a local muscle effect rather than a central cardiorespiratory mechanism.
Alleles↗
Cloning of an EF-P homologue from Bacteroides fragilis that increases B. fragilis glutamine synthetase activity in Escherichia coli.
Investigations of possible regulators of Bacteroides fragilis glutamine synthetase (GS) activity were done in Escherichia coli using a compatible dual-plasmid system. The B. fragilis glnA gene, together with upstream and downstream flanking regions, was cloned onto the low copy number plasmid pACYC184 and expressed in the E. coli glnA ntrB ntrC deletion strain, YMC11. GS activity was monitored following co-transformation with a B. fragilis genomic library carried on the compatible plasmid pEcoR251. A gene was cloned that caused a twofold increase in B. fragilis GS activity but did not affect the activity of the E. coli GS enzyme or the B. fragilis sucrase (ScrL). Deletion of the B. fragilis glnA downstream region decreased basal levels of GS activity, but did not affect the ability of the cloned gene to increase the B. fragilis GS activity. Reporter gene analysis, using the B. fragilis glnA promoter region fused to the promoterless Clostridium acetobutylicum endoglucanase gene, showed no increase in reporter gene activity. This demonstrated that the increase in GS activity was not regulated at the transcriptional level, and that the cloned gene product was not affecting the copy number of the plasmid in trans. Sequence data indicated that the cloned gene had good amino acid identity to a range of elongation factor P (EF-P) proteins, the highest being to that of a Synechocystis sp (48%), and the least to Mycobacterium genitalium (27%). Amino acid identity to the E. coli EF-P was intermediate (37%). A possible role for EF-P in enhancing translation of the B. fragilis glnA mRNA is proposed.
Amino Acid Sequence↗
The origin and loss of the ubiquitin activating enzyme gene on the mammalian Y chromosome.
Mammalian sex chromosomes are thought to be descended from a homologous pair of autosomes: a testis-determining allele which defined the Y chromosome arose, recombination between the nascent X and Y chromosomes became restricted and the Y chromosome gradually lost its non-essential genetic functions. This model was originally inferred from the occurrence of few Y-linked genetic traits, pairing of the X and Y chromosomes during male meiosis and, more recently, the existence of X-Y homologous genes. The comparative analysis of such genes is a means by which the validity of this model can be evaluated. One well-studied example of an X-Y homologous gene is the ubiquitin activating enzyme gene ( UBE1 ), which is X-linked with a distinct Y-linked gene in many eutherian ('placental') and metatherian (marsupial) mammals. Nonetheless, no UBE1 homologue has yet been detected on the human Y chromosome. Here we describe a more extensive study of UBE1 homologues in primates and a prototherian mammal, the platypus. Our findings indicate that UBE1 lies within the X-Y pairing segment of the platypus but is absent from the human Y chromosome, having been lost from the Y chromosome during evolution of the primate lineage. Thus UBE1 illustrates the key steps of 'autosomal to X-specific' evolution of genes on the sex chromosomes.
Animals↗
Characterisation of a transposon-induced pleiotropic mutant of Clostridium acetobutylicum P262.
Transposon-induced metronidazole resistance was used as a selection system for the isolation of Clostridium acetobutylicum P262 mutants with altered electron transport pathways. The metronidazole resistant transconjugant of interest, mutant 3R, displayed resistance to DNA damaging agents, UV and bleomycin, and harboured a single transposon insertion within a structural gene, designated sum(susceptibility to metronidazole). The sum gene encoded a 334 amino-acid protein, with 36% identity and 57-58% similarity at the amino acid level to two archaebacterial protein sequences which appear to represent a class of uncharacterised reductase enzymes. Physiological studies of mutant 3R revealed a number of pleiotropic characteristics which included enhanced autolysin activity, increased motility, impaired clostridial cell formation, and resistance to the toxic tripeptide analogue, bialaphos. The introduction of the sum gene in multiple copies on a plasmid vector into the related strain Clostridium beijerinckii NCIMB 8052, resulted in inhibition of cell division, motility and autolysin activity. The sum gene appears to be a member of a new subgroup of activases with reducing activity, which may control a regulon affecting different stationary phase processes such as clostridial differentiation and sporulation in C. acetobutylicum P262. The metronidazole resistant phenotype of the sum mutant can be attributed to an increased capacity for DNA repair.
Journal Article↗
Structure and transcription of genes within the beta-hbd-adh1 region of Clostridium acetobutylicum P262.
The 1.2-kb DNA fragment upstream of the linked beta-hbd (3-hydroxybutyryl-CoA dehydrogenase) and adh1 (NADPH-dependent alcohol dehydrogenase) genes from Clostridium acetobutylicum P262 was sequenced. The upstream region contained an open reading frame (ORFB) which was found to have 44% amino acid identity to the fixB gene products of Rhizobium and Azorhizobium. The beta-hbd and ORFB genes were expressed during the acidogenic and solventogenic phases. The beta-hbd gene was transcribed on a single mRNA species of 2.0 kb, whereas the ORFB gene was transcribed on two species of mRNA of 2.0 and 3.5 kb, respectively. The adh1 gene was induced or derepressed at the pH breakpoint before the onset of solventogenesis and was transcribed on a single species of mRNA of 2.4 kb.
3-Hydroxyacyl CoA Dehydrogenases↗
The genetic engineering of microbial solvent production.
Although the production of acetone and butanol by Clostridium strains was a thriving industrial fermentation process, it is no longer competitive with the chemical synthesis of solvents and has been discontinued. However, studies on the molecular biology of Clostridium strains suggest that genetic engineering for improved solvent production is feasible, and could result in the revival of the industrial fermentation process.
1-Butanol↗
Mode of action of metronidazole and a Bacteroides fragilis metA resistance gene in Escherichia coli.
The in-vivo mode of action of metronidazole and the MetA protein which confers resistance to metronidazole, was investigated in Escherichia coli wild type and DNA repair-deficient strains. All the E. coli strains were moderately susceptible to metronidazole under aerobic conditions but were more susceptible under anaerobic conditions, and the amount of DNA breakage was less under anaerobic than aerobic conditions. E. coli excision (uvr) and recombination (rec) mutants were more susceptible than DNA repair wild type strains. Metronidazole did not induce cell lysis in E. coli but caused single strand DNA breaks in wild type and repair-deficient E. coli strains. The MetA protein reduced DNA breakage caused by metronidazole in E. coli wild type and DNA repair-deficient strains grown under aerobic and anaerobic conditions, and inhibited the suppressor effect of the RecE protein in E. coli recBC strains. The MetA protein did not inactivate metronidazole.
Aerobiosis↗
Characterization and expression of the hydrogenase-encoding gene from Clostridium acetobutylicum P262.
The hydrogenase enzyme of Clostridium acetobutylicum plays a pivotal role in controlling electron flow, and hence carbon flow, during the complex biphasic fermentation of carbohydrates to the neutral solvents acetone and butanol. We report here the cloning and molecular characterization of the hydrogenase-encoding gene (hydA) from C. acetobutylicum P262. This gene was isolated by colony hybridization, using the Clostridium pasteurianum hydrogenase-1 gene as a probe. The DNA sequence encoding the hydA gene from C. acetobutylicum was determined, and revealed an ORF (1722 bp) encoding a 574 amino-acid protein. This C. acetobutylicum hydrogenase protein product has 82% similarity and 67% identity with the C. pasteurianum hydrogenase-1 protein. Northern blot analysis of RNA isolated from C. acetobutylicum indicates that the C. acetobutylicum hydrogenase protein product is translated from a monocistronic operon. RNA was isolated from the different morphological and physiological stages of a batch C. acetobutylicum fermentation, and further Northern blot analyses revealed no differences in the expression of the gene during acidogenesis as opposed to solventogenesis. Primer extension experiments confirmed these results and identified the 5' start of the mRNA transcript. These results correlated well with the physiological need for this organism to dispose of excess reducing equivalents.
Amino Acid Sequence↗
A Clostridium acetobutylicum regulator gene (regA) affecting amylase production in Bacillus subtilis.
Plasmid pMET7C containing a 6.05 kb DNA insert from Clostridium acetobutylicum P262 made Escherichia coli F19 cells sensitive to metronidazole. The nucleotide sequence of the C. acetobutylicum DNA controlling metronidazole sensitivity in E. coli F19 revealed an ORF of 972 bp which encoded a protein of 324 amino acids with a calculated Mr of 35,000. The amino acid sequence encoded by the ORF contained a helix-turn-helix DNA-binding domain and was homologous to the catabolite control protein, CcpA, from Bacillus subtilis and Bacillus megaterium, a tRNA repressor of E. coli encoded by the shl gene, and the GalR, Lacl and PurR repressors of E. coli. The C. acetobutylicum ORF, which was termed regA, complemented a B. subtilis ccpA mutant and an E. coli shl mutant, but was unable to complement E. coli galR, lacl or purR mutants. To determine whether the regA gene product was involved in the regulation of amylase gene expression in C. acetobutylicum, a starch-degrading enzyme gene (staA) from C. acetobutylicum NCIMB 8052 was cloned. The RegA protein inhibited the degradation of starch by the C. acetobutylicum staA gene product in E. coli.
Acetoin↗
Regulation of nitrogen metabolism, starch utilisation and the beta-hbd-adh1 gene cluster in Clostridium acetobutylicum.
The successful genetic manipulation of Clostridium acetobutylicum for the increased production of solvents will depend on an understanding of gene structure and regulation in the bacterium. The glutamine synthetase (glnA) gene is regulated by antisense RNA, transcribed from a downstream promoter, in the opposite direction to the glnA gene. An open reading frame (ORF) was detected downstream of the glnA gene, which has sequence homology to response regulators with anti-termination activity and may be involved in sensing nitrogen conditions. The expression of the linked beta-hbd, adh1 and fixB genes was investigated throughout the bacterial growth cycle by RNA hybridisation techniques. The adh1 gene was independently expressed as a 2.4-kb transcript which peaked at 12 h, immediately prior to the solventogenic phase. The beta-hbd and fixB genes were transcribed throughout the acidogenic and solventogenic phases. A regulator gene, regA, which complements a Bacillus subtilis ccpA mutant, has been identified and sequenced from C. acetobutylicum P262. The regA gene repressed the degradation of starch by an uncharacterised C. acetobutylicum gene, and may therefore play a role in the utilisation of carbohydrate substrates in this organism.
Amino Acid Sequence↗