MadSci Network: Biochemistry

Re: Glycolysis: How does NAD*H 'know' oxygen is present in the mitochondria

Date: Tue Nov 10 13:27:25 1998
Posted By: Terry Hebert, Faculty, Universite de Montreal, Biochemistry, Montréal Heart Institute
Area of science: Biochemistry
ID: 910484352.Bc

	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 
	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 
	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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