|Lecture Notes: 18 April||
The reactions of fatty acid synthesis all take place in the cytosol, but acetyl-CoA is made in the mitochondria and can't cross the inner membrane. The Pyruvate-Malate Cycle (Citrate-Pyruvate Cycle) [overhead] (packet) is used to take acetyl- groups to the cytosol while simultaneously providing a source of NADPH from NADH, and thus coupling fatty acid synthesis to Glycolysis. Note that the acetyl-CoA is first joined to oxaloacetate to make citrate which is readily transported out of the mitochondria using a co-transporter. The citrate is then cleaved to acetyl-CoA and oxaloacetate, a process requiring ATP to make it favorable (recall the condensation was spontaneous). Acetyl-CoA for fatty acid synthesis is now available in the cytosol, but oxaloacetate must be regenerated for the mitosol.
The cytosolic oxaloacetate is now dehydrogenated to give malate and NAD+. Malate is next oxidized by Malic enzyme to give pyruvate in a reaction which also provides NADPH for use in biosynthesis. (Note that NADH generated in Glycolysis is "converted" to NADPH for F.A. synthesis in these two reactions, while simultaneously regenerating the NAD+ needed to continue Glycolysis!) The pyruvate can now cross into the mitosol to be used in regenerating oxaloacetate.
Now we have all of the pieces of fatty acid biosynthesis starting from glucose. Let's look at the integration of the various pathways involved: Glycolysis, hexose monophosphate shunt, Pyruvate-malate shuttle, and Fatty acid biosynthesis. Notice the provision of reducing equivalents, redox balance and provision of required cytosolic ATP's as well as carbon source.
FYI - Fatty Acid Modification
ELONGATION OF FATTY ACIDS
Fatty acid metabolism is regulated both hormonally and via feed-back inhibition and feed-forward activation. Thus mobilization of free fatty acids from the adipose tissue results from low insulin levels. The free fatty acids are then transported through the blood to the rest of the body including the liver. In the liver fatty acid oxidation and ketone body synthesis is activated by glucagon. Note that glucagon and insulin levels are opposite: high insulin =low glucagon and vice-versa. So for low insulin will also have high glucagon, thus fatty acids will be released from the adipose and will be converted in the liver into ketone bodies.
The regulation of fatty acid oxidation, fatty acid synthesis and ketone body synthesis in the liver is summarized in the figure:
Note that a LACK of insulin results in a release of fatty acids from adipose.
Protein catabolism and anabolism are often out of sync - either no additional protein is needed or the amino acid composition of the synthesized proteins is not identical to the protein being hydrolyzed. Neither protein nor amino acids are stored as such. Thus organisms must frequently degrade excess amino acids. Two paths may be available: deaminate the unneeded amino acids and breakdown the carbon skeletons for energy or for storage as fat or carbohydrate and eliminate the nitrogen; or the nitrogen may be transferred to another carbon backbone to make a needed amino acid.
Nitrogen can be eliminated in a variety of forms, depending on the physiological conditions experienced by the organism:
Amino Acid Deamination: For any of these products nitrogen must first be removed from the amino acids. Ammonia is often an intermediate if not the final product in all of these organisms. Most ammonia results from the deamination of a single amino acid: glutamate, via the Glutamate dehydrogenase reaction:
This enzyme is somewhat unusual in that it can use either NADH or NADPH. Glutamate DH is activated by ADP and inhibited by GTP in vitro so they may regulate it in vivo. Of course these nucleotides would not provide a highly sensitive regulation, activity would only loosely follow energy charge.
Last modified 18 April 2007