Catalytic and mechanical cycles in F-ATP synthases. Fourth in the Cycles Review Series.
Cycles have a profound role in cellular life at all levels of organization. Well-known cycles in cell metabolism include the tricarboxylic acid and the urea cycle, in which a specific carrier substrate undergoes a sequence of chemical transformations and is regenerated at the end. Other examples include the interconversions of cofactors, such as NADH or ATP, which are present in the cell in limiting amounts and have to be recycled effectively for metabolism to continue. Every living cell performs a rapid turnover of ATP to ADP to fulfil various energetic demands and effectively regenerates the ATP from ADP in an energy-consuming process. The turnover of the ATP cycle is impressive; a human uses about its body weight in ATP per day. Enzymes perform catalytic reaction cycles in which they undergo several chemical and physical transformations before they are converted back to their original states. The ubiquitous F1F(o) ATP synthase is of particular interest not only because of its biological importance, but also owing to its unique rotational mechanism. Here, we give an overview of the membrane-embedded F(o) sector, particularly with respect to the recent crystal structure of the c ring from Ilyobacter tartaricus, and summarize current hypotheses for the mechanism by which rotation of the c ring is generated.
EMBO Rep. 2006 Mar;7(3):276-82
Ribose accelerates the repletion of the ATP pool during recovery from reversible ischemia of the rat myocardium.
It is a characteristic feature of the myocardium that the derangement in function  and the depletion of the ATP pool [1, 2, 9] that occur subsequent to oxygen deficiency persist when blood flow is restored. Of renewed interest is the inability of the heart to replenish rapidly its adenine nucleotide pool once it has been diminished during a brief period of regional ischemia [2, 9]. A hypothesis that could explain this metabolic insufficiency of the myocardium is that the biosynthesis of adenine nucleotides is very slow in the normal heart and is increased only moderately during postischemic recovery  so that the replenishment of adenine nucleotides is not affected appreciably. To substantiate such a hypothesis it is necessary to provide evidence that the restitution of the ATP pool can be accelerated by stimulation of this biosynthetic process. In previous studies ribose has been recognized as a substrate that enhances markedly adenine nucleotide biosynthesis in the rat heart [11, 12]. We now demonstrate that continuous i.v. infusion of ribose during recovery from a 15-min period of myocardial ischemia in rats leads to restoration of the cardiac ATP pool within 12 h, whereas 72 h are needed for ATP normalization without any intervention.
J Mol Cell Cardiol. 1984 Sep;16(9):863-6
Influence of ribose on adenine salvage after intense muscle contractions.
The influence of ribose supplementation on skeletal muscle adenine salvage rates during recovery from intense contractions and subsequent muscle performance was evaluated using an adult rat perfused hindquarter preparation. Three minutes of tetanic contractions (60 tetani/min) decreased ATP content in the calf muscles by approximately 50% and produced an equimolar increase in IMP. Effective recovery of muscle ATP 1 h after contractions was due to reamination of IMP via the purine nucleotide cycle and was complete in the red gastrocnemius but incomplete in the white gastrocnemius muscle section. Adenine salvage rates in recovering muscle averaged 45 +/- 4, 49 +/- 5, and 30 +/- 3 nmol. h(-1). g(-1) for plantaris, red gastrocnemius, and white gastrocnemius muscle, respectively, which were not different from values in corresponding nonstimulated muscle sections. Adenine salvage rates increased five- to sevenfold by perfusion with approximately 4 mM ribose (212 +/- 17, 192 +/- 9, and 215 +/- 14 nmol. h(-1). g(-1) in resting muscle sections, respectively). These high rates were sustained in recovering muscle, except for a small (approximately 20%) but significant (P < 0.001) decrease in the white gastrocnemius muscle. Ribose supplementation did not affect subsequent muscle force production after 60 min of recovery. These data indicate that adenine salvage rates were essentially unaltered during recovery from intense contractions.
J Appl Physiol. 2001 Oct;91(4):1775-81
Effect of ribose supplementation on resynthesis of adenine nucleotides after intense intermittent training in humans.
The effect of oral ribose supplementation on the resynthesis of adenine nucleotides and performance after 1 wk of intense intermittent exercise was examined. Eight subjects performed a random double-blind crossover design. The subjects performed cycle training consisting of 15 x 10 s of all-out sprinting twice per day for 7 days. After training the subjects received either ribose (200 mg/kg body wt; Rib) or placebo (Pla) three times per day for 3 days. An exercise test was performed at 72 h after the last training session. Immediately after the last training session, muscle ATP was lowered (P < 0.05) by 25 +/- 2 and 22 +/- 3% in Pla and Rib, respectively. In both Pla and Rib, muscle ATP levels at 5 and 24 h after the exercise were still lower (P < 0.05) than pretraining. After 72 h, muscle ATP was similar (P > 0.05) to pretraining in Rib (24.6 +/- 0.6 vs. 26.2 +/- 0.2 mmol/kg dry wt) but still lower (P < 0.05) in Pla (21.1 +/- 0.5 vs. 26.0 +/- 0.2 mmol/kg dry wt) and higher (P < 0.05) in Rib than in Pla. Plasma hypoxanthine levels after the test performed at 72 h were higher (P < 0.05) in Rib compared with Pla. Mean and peak power outputs during the test performed at 72 h were similar (P > 0.05) in Pla and Rib. The results support the hypothesis that the availability of ribose in the muscle is a limiting factor for the rate of resynthesis of ATP. Furthermore, the reduction in muscle ATP observed after intense training does not appear to be limiting for high-intensity exercise performance.
Am J Physiol Regul Integr Comp Physiol. 2004 Jan;286(1):R182-8
D-Ribose improves diastolic function and quality of life in congestive heart failure patients: a prospective feasibility study.
Patients with chronic coronary heart disease often suffer from congestive heart failure (CHF) despite multiple drug therapies. D-Ribose has been shown in animal models to improve cardiac energy metabolism and function following ischaemia. This was a prospective, double blind, randomized, crossover design study, to assess the effect of oral D-ribose supplementation on cardiac hemodynamics and quality of life in 15 patients with chronic coronary artery disease and CHF. The study consisted of two treatment periods of 3 weeks, during which either oral D-ribose or placebo was administered followed by a 1-week wash out period, and then administration of the other supplement. Assessment of myocardial functional parameters by echocardiography, quality of life using the SF-36 questionnaire and functional capacity using cycle ergometer testing was performed. The administration of D-ribose resulted in an enhancement of atrial contribution to left ventricular filling (40+/-11 vs. 45+/-9%, P=0.02), a smaller left atrial dimension (54+/-20 vs. 47+/-18 ml, P=0.02) and a shortened E wave deceleration (235+/-64 vs. 196+/-42, P=0.002) by echocardiography. Further, D-ribose also demonstrated a significant improvement of the patient’s quality of life (417+/-118 vs. 467+/-128, P< or =0.01). In comparison, placebo did not result in any significant echocardiographic changes or in quality of life. This feasibility study in patients with coronary artery disease in CHF revealed the beneficial effects of D-ribose by improving diastolic functional parameters and enhancing quality of life.
Eur J Heart Fail. 2003 Oct;5(5):615-9
D-Ribose as a supplement for cardiac energy metabolism.
Metabolic support for the heart has been an attractive concept since the pioneering work of Sodi-Pallares et al. four decades ago.* Recently, interest has increased in the use of over-the-counter supplements and naturally occurring nutriceuticals for enhancement of cardiac and skeletal muscle performance. These include amino acids such as creatine, L-carnitine, and L-arginine, as well as vitamins and cofactors such as alpha-tocopherol and coenzyme Q. Like these other molecules, D-ribose is a naturally occurring compound. It is the sugar moiety of ATP and has also received interest as a metabolic supplement for the heart. The general hypothesis is that under certain pathologic cardiac conditions, nucleotides (particularly ATP, ADP, and AMP) are degraded and lost from the heart. The heart’s ability to resynthesize ATP is then limited by the supply of D-ribose, which is a necessary component of the adenine nucleotide structure. In support of this hypothesis, recent reports have used D-ribose to increase tolerance to myocardial ischemia. Its use in patients with stable coronary artery disease improves time to exercise-induced angina and electrocardiographic changes. In conjunction with thallium imaging or dobutamine stress echocardiography, D-ribose supplementation has been used to enhance detection of hibernating myocardium. In this article, we review the biochemical basis for using supplemental D-ribose as metabolic support for the heart and discuss the experimental evidence for its benefit.
J Cardiovasc Pharmacol Ther. 2000 Oct;5(4):249-58
Ischemic heart disease: metabolic approaches to management.
The number of patients with coronary artery disease and its risk factors is increasing in Western nations. New treatments for these patients may soon include a class of agents known as the metabolic modulators. This group of agents consists of the partial fatty acid oxidation inhibitors trimetazidine and ranolazine, as well as dichloroacetate, which promotes carbohydrate utilization. Metabolic modulators also include the nutriceuticals L-carnitine and D-ribose. The available evidence regarding the benefits of each of these five agents is reviewed.
Clin Cardiol. 2004 Aug;27(8):439-41
Effects of ribose on exercise-induced ischaemia in stable coronary artery disease.
There is no established treatment specifically aimed at protecting or restoring cardiac energy metabolism, which is greatly impaired by ischaemia. Even after reperfusion, myocardial content of ATP remains low for more than 72 h. Long-term post-ischaemic dysfunction and irreversibility of ischaemic damage have been associated with low ATP content. Evidence that the pentose sugar ribose stimulates ATP synthesis and improves cardiac function led us to test the possibility that ribose increases tolerance to myocardial ischaemia in patients with coronary artery disease (CAD). 20 men with documented severe CAD underwent two symptom-limited treadmill exercise tests on 2 consecutive days; we postulated that the ischaemia induced might bring about changes in ATP metabolism lasting for several days. Patients whose baseline tests showed reproducibility were randomly allocated 3 days of treatment with placebo or ribose 60 g daily in four doses by mouth. Exercise testing was repeated after treatment on day 5. At that time mean (95% confidence interval) treadmill walking time until 1 mm ST-segment depression was significantly greater in the ribose than in the placebo group (276 [220-331] vs 223 [188-259] s; p = 0.002). The groups did not differ significantly in time to moderate angina. In the ribose-treated group the changes from baseline to day 5 in both time to ST depression and time to moderate angina were significant (p less than 0.005), but these changes were not significant in the placebo group. In patients with CAD, administration of ribose by mouth for 3 days improved the heart’s tolerance to ischaemia. The presumed effects on cardiac energy metabolism offer new possibilities for adjunctive medical treatment of myocardial ischaemia.
Lancet. 1992 Aug 29;340(8818):507-10
The benefits of ribose in cardiovascular disease.
Cardiovascular disease still ranks as the leading cause of death in men and women. Adults have tried to lower their risk of cardiovascular disease by improving their diet, quitting smoking, controlling blood pressure and exercising regularly. Additionally, many adults have turned to nutriceutical or natural products. Myocardial ischemia, produces a depression in myocardial tissue levels of high energy compounds, along with a compromise in myocardial function. Ribose, a naturally occurring sugar, has been extensively investigated, both in animal and clinical studies, as an agent to enhance the recovery of these depressed energy compounds. Results of these studies have been promising in enhancing the recovery of these energy molecules along with an improvement in myocardial function. Therefore, ribose should be considered as a potential agent in the treatment of ischemic cardiovascular disease.
Med Hypotheses. 2003 Feb;60(2):149-51
Ribose infusion accelerates thallium redistribution with early imaging compared with late 24-hour imaging without ribose.
To determine if early (4-h) thallium-201 imaging with ribose infusion would enhance detection of thallium redistribution better than late (24-h) imaging without ribose infusion, 15 patients with coronary artery disease underwent thallium stress tests by both methods within 2 weeks. All 15 patients had quantitative coronary angiography. After immediate postexercise planar imaging during the first of two exercise tests, patients were randomized to receive either intravenous ribose (3.3 mg/kg per min) or a control infusion of saline solution for 30 min. Images performed at 4 h for the ribose study were compared with those at 24 h for the saline control study. During the second test, exercise was carried to the same rate-pressure product and each patient received the opposite infusion. Four-hour postexercise images after ribose infusion identified 21 reversible defects not seen in the 24-h saline study. Three reversible defects were seen only in saline studies, but not with ribose at 4 h (p less than 0.01); 15 reversible defects were seen with both tests. When analyzed with respect to the 31 vascular territories supplied by a coronary artery with a greater than 50% stenosis, 8 territories had reversible defects present in the ribose but not the saline study and the saline study did not demonstrate reversible defects in territories that were seen in the ribose study (p less than 0.01). In 14 of these territories, reversible defects were seen with both tests. In 6 of 15 patients, additional vascular territories with reversible defects were identified after ribose infusion. It is concluded that ribose enhances the detection of thallium redistribution at 4 h compared with 24-h control images in patients with coronary artery disease and, therefore, substantially improves the identification of viable ischemic myocardium.
J Am Coll Cardiol. 1991 Dec;18(7):1671-81
Ribose facilitates thallium-201 redistribution in patients with coronary artery disease.
To investigate whether i.v. infusion of ribose, an adenine nucleotide precursor, postischemia facilitates thallium-201 (201Tl) redistribution and improves identification of ischemic myocardium in patients with coronary artery disease (CAD), 17 patients underwent two exercise 201Tl stress tests, performed 1-2 wk apart. After immediate postexercise planar imaging, patients received either i.v. ribose (3.3 mg/kg/min x 30 min) or saline as a control. Additional imaging was performed 1 and 4 hr postexercise. Reversible defects were identified by count-profile analysis. Significantly more (nearly twice as many) reversible 201Tl defects were identified on the post-ribose images compared to the post-saline (control) images at both 1 and 4 hr postexercise (p less than 0.001). Quantitative analyses of the coronary arteriogram was available in 13 patients and confirmed that the additional reversible defects were in myocardial regions supplied by stenosed arteries. We conclude that ribose appears to facilitate 201Tl redistribution in patients with CAD and enhances identification of ischemic myocardium.
J Nucl Med. 1991 Feb;32(2):193-200
Effects of ribose supplementation on repeated sprint performance in men.
This study used a randomized, placebo-controlled, crossover design to evaluate the effects of oral ribose supplementation on short-term anaerobic performance. After familiarization, subjects performed 2 bouts of repeated cycle sprint exercise (six 10-second sprints with 60-second rest periods between sprints) in a single day. After the second exercise, bout subjects ingested 32 g of ribose or cellulose (4 x 8-g doses) during the next 36 hours. After supplementation, subjects returned to the laboratory to perform a single bout of cycle sprinting (as described above). After a 5-day washout period, subjects repeated the protocol, receiving the opposite supplement treatment. Ribose supplementation lead to statistically significant increases in mean power and peak power in sprint 2 (10.9 and 6.6%, respectively) and higher (although not significant) absolute values in sprints 1, 3, and 4. In conclusion, ribose supplementation did not show reproducible increases in performance across all 6 sprints. Therefore, within the framework of this investigation, it appears that ribose supplementation does not have a consistent or substantial effect on anaerobic cycle sprinting.
J Strength Cond Res. 2003 Feb;17(1):47-52
Ribose versus dextrose supplementation, association with rowing performance: a double-blind study.
OBJECTIVE: It has been hypothesized that ribose supplementation rapidly replenishes adenosine triphosphate stores and thereby improves exercise performance. We compared the effects of ribose versus dextrose on rowing performance. DESIGN: Double-blind randomized trial. SETTING: Rowing team training area of large midwestern university. PARTICIPANTS: Thirty-one women collegiate rowers. INTERVENTIONS: We studied the effects of ribose versus dextrose supplementation (10 g each in 8 oz water) for 8 weeks before and after practice and 2000-m time trials. OUTCOME MEASUREMENTS AND RESULTS: In the time trials, the dextrose group showed significantly more improvement at 8 weeks than the ribose group (median, 15.2 vs. 5.2 s; P = 0.031). CONCLUSIONS: We doubt ribose impaired, and hypothesize dextrose enhanced, rowing performance. Further research is needed to define what role, if any, dextrose and ribose play as athletic supplements.
Clin J Sport Med. 2006 Jan;16(1):68-71