|MadSci Network: Biochemistry|
Hi! Your question is an interesting one. It's been a long time since I had to think about intermediary metabolism! OK, first things first. We know that one of the products of glycolysis (the anaerobic arm of glucose breakdown) is two molecules of NADH. The NADH can then be used in oxidative phosphorylation to produce ATP. How does the system know when to use oxidative phosphorylation? Well, it all depends on the energy status of the cell. As you know, ATP is the "fuel" used for most cellular processes. If the cell it at rest it requires little energy so the relative levels of ATP/ADP are high whereas if the cell is extremely active as in heart muscle, for example this ratio is low. In both glycolysis and the Kreb's cycle there are a number of control points that are sensitive to the energy status of the cell. In glycolysis, one of these checkpoints is at the enzyme pyruvate kinase which converts phosphoenolpyruvate to pyruvate and ATP. ATP actually inhibits this enzyme in a process called feedback inhibition, i.e. where the product actually shuts down the machine which makes it. ATP also inhibits phosphofructokinase, which is the key regulatory step in glycolysis. At the level of the Kreb's cycle there are three checkpoints sensitive to ATP levels: 1) Citrate synthase which converts oxaloacetate to citrate and is inhibited by ATP. 2) Isocitrate dehydrogenase which converts isocitrate to alpha- ketoglutararte and is inhibited by ATP and stimulated by ADP. 3) alpha-ketoglutarate dehydrogenase which converts alpha-KG to succinyl CoA and is inhibited by it's product or by NADH. Remember, NADH does not cross into the mitochondria but takes electrons transferred from NADH to the shuttle reaction (the conversion of dihdroxyacetone phosphate to glycerol 3-phosphate). Glycerol 3-P can permeate the mitochondrial membrane where it releases it electrons to FAD. In heart and liver, another shuttle is used- the malate/aspartate shuttle which involves four enzymes and two membrane carriers but works again via exchange of electrons. The most important factor in determing the rate of oxidative phosphorylation is the level of ADP. The availability of NAD or FAD signal that the energy charge of the cell is low and thus allows the citric acid cycle to proceed to completion in the presense of oxygen, ADP and inorganic phosphate (used to make ATP from ADP). Electrons do not flow in the electron transport chain unless the resulting proton gradient in alleviated by ADP being phosphorylated to ATP. Thus the energy status of the cell determines the net rate of ATP synthesis.
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