ATP formation

This is true of skeletal muscle, particularly the white fibers, where the rate of work output—and therefore the need for ATP formation—may exceed the rate at which oxygen can be taken up and utilized. Glycolysis in erythrocytes, even under aerobic conditions, always terminates in lactate, because the subsequent reactions of pymvate are mitochondrial, and erythrocytes lack mitochondria. Other tissues that normally derive much of their energy from glycolysis and produce lactate include brain, gastrointestinal tract, renal medulla, retina, and skin. The liver, kidneys, and heart usually take up... 

Condensation of CO2, ammonia, and ATP to form carbamoyl phosphate is catalyzed by mitochondrial carbamoyl phosphate synthase I (reaction 1, Figure 29-9). A cytosolic form of this enzyme, carbamoyl phosphate synthase II, uses glutamine rather than ammonia as the nitrogen donor and functions in pyrimidine biosynthesis (see Chapter 34). Carbamoyl phosphate synthase I, the rate-hmiting enzyme of the urea cycle, is active only in the presence of its allosteric activator JV-acetylglutamate, which enhances the affinity of the synthase for ATP. Formation of carbamoyl phosphate requires 2 mol of ATP, one of which serves as a phosphate donor. Conversion of the second ATP to AMP and pyrophosphate, coupled to the hydrolysis of pyrophosphate to orthophosphate, provides the driving... 

H2 as a reductant (Fe, Ni) in anaerobic archaea Energy capture related to ATP formation (Fe, NADH, flavin, quinones)... 

The spatial separation between the components of the electron transport chain and the site of ATP synthesis was incompatible with simple interpretations of the chemical coupling hypothesis. In 1964, Paul Boyer suggested that conformational changes in components in the electron transport system consequent to electron transfer might be coupled to ATP formation, the conformational coupling hypothesis. No evidence for direct association has been forthcoming but conformational changes in the subunits of the FI particle are now included in the current mechanism for oxidative phosphorylation. 

By 1960 it seemed likely that vesicles (sealed membrane preparations) were essential for ATP formation to occur. R.J.P. Williams (1959-1961 see 1993) postulated that complex assemblies of catalysts, as in the cytochrome chain, would allow spatial separation of reaction products within the mitochondrial membrane. The initial site of reaction with... 

Williams, R.J.P. (1993). The history of Proton-driven ATP formation. Bioscience Reports 13,191-212. 

However, if the heat produced is not sufficient to maintain the temperature, despite decreased heat loss, it can be produced by specific processes. These are shivering, substrate cycling or uncoupling of ATP formation from electron transfer in mitochondria. 

In some cases, mutations that result in partial loss of a protein or its activity only cause major problems in adult life. This is explained by the fact that maximum rates of many processes (e.g. ATP formation in muscle) are rarely required by humans in developed countries, so that the rate of the process is sufficient to satisfy most, if not all, of the activities essential to life. However, progressive damage to DNA throughout life may convert a partial deficiency into a total deficiency. This can result in an adult deficiency disease, since symptoms only develop in the adult. 

Once the phosphate ester is hydrolysed, there is an immediate rapid tautomerism to the keto form, which becomes the driving force for the metabolic transformation of phosphoenolpyruvic acid into pyruvic acid, and explains the large negative free energy change in the transformation. This energy release is coupled to ATP formation (see Box 7.25). 

NADH oxidation via complex I takes place on the inside of the membrane—i. e., in the matrix space, where the tricarboxylic acid cycle and 3-oxidation (the most important sources of NADH) are also located. O2 reduction and ATP formation also take place in the matrix. 

Muscle-specific auxiliary reactions for ATP synthesis exist in order to provide additional ATP in case of emergency. Creatine phosphate (see B) acts as a buffer for the ATP level. Another ATP-supplying reaction is catalyzed by adenylate kinase [1] (see also p.72). This disproportionates two molecules of ADP into ATP and AMP. The AMP is deaminated into IMP in a subsequent reaction [2] in order to shift the balance of the reversible reaction [1 ] in the direction of ATP formation. 

An enzymatic reaction intermediate formed by phospho-ryl transfer to a carboxyl group on an enzyme. Acyl-phosphates are structurally analogous to acid anhydrides (R—CO —O —CO—R ), and they are thermodynamically less stable than either of the two phosphoanhydride bonds in ATP. This is evident by the fact that the acetate kinase reaction (ADP + acetyl-phosphate = ATP + acetate) favors ATP formation with an equilibrium constant of about 3,000. Acetyl-phosphate can be chemically synthesized by reacting orthophosphate with acetic anhydride. 

A measure of oxidative phosphorylation, equal to the ratio of the number phosphate groups esterified (i.e., ATP formation from ADP and phosphate) relative to the atoms of oxygen consumed by the mitochondria. 

Oxidizible substrates from glycolysis, fatty acid or protein catabolism enter the mitochondrion in the form of acetyl-CoA, or as other intermediaries of the Krebs cycle, which resides within the mitochondrial matrix. Reducing equivalents in the form of NADH and FADH pass electrons to complex I (NADH-ubiquinone oxidore-ductase) or complex II (succinate dehydrogenase) of the electron transport chain, respectively. Electrons pass from complex I and II to complex III (ubiquinol-cyto-chrome c oxidoreductase) and then to complex IV (cytochrome c oxidase) which accumulates four electrons and then tetravalently reduces O2 to water. Protons are pumped into the inner membrane space at complexes I, II and IV and then diffuse down their concentration gradient through complex V (FoFi-ATPase), where their potential energy is captured in the form of ATP. In this way, ATP formation is coupled to electron transport and the formation of water, a process termed oxidative phosphorylation (OXPHOS). 

B. The ATP synthase inhibitor oligomycin binds directly to the enzyme complex and plugs up the H channel, which blocks ATP formation. 

C. Uncoupling agents provide an alternate pathway to transfer protons back into the mitochondrial matrix, which dissipates the proton gradient and bypasses ATP formation by the ATPase. 

Albendazole selectively blocks glucose uptake and depletes glycogen stores. ATP formation is thus inhibited. It should be administered on an empty stomach for intraluminal parasites and with a fatty meal for tissue parasites. It is metabolized to an active sulfoxide metabolite resulting in very low Albendazole blood levels. Albendazole sulfoxide is excreted in the urine with an elimination half-life of about 8 h. Used for 1-3 days in doses recommended for intestinal worms the incidence of adverse effects is similar in treatment and control groups. Hepato-toxicity may occur, especially after the higher doses that are needed for hydatid disease. Also alopecia has been reported. 

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