Glucose is first degraded to pyruvate by aerobic glycolysis in the cytoplasm.
Pyruvate is then transported into the mitochondria, where its oxidation forms mitochondrial acetyl CoA and other products. Also formed by catabolism of fatty acids, ketone bodies and certain amino acids.
Acetyl CoA can then serve as a substrate for citrate synthesis.
Citrate, in turn, can be transported out of the mitochondria to the cytoplasm (where fatty acid synthesis occurs), and there split to generate cytoplasmic acetyl CoA for fatty acid synthesis. Enzyme is ATP Citrate Lyase.
In the seventh reaction the double bond is reduced by NADPH, yielding a saturated fatty acyl group two carbons longer than the initial one (an acetyl group was converted to a butyryl group in this case): 2-butenoyl-ACP + NADPH + H + -> butyryl-ACP + NADP +
The butyryl group is then transferred from the ACP sulfhydryl group to the CE sulfhydryl:
1-In the intermembrane space of the mitochondria, fatty acyl CoA reacts with carnitine in a reaction catalyzed by carnitine acyltransferase I (CAT-I), yielding CoA and fatty acyl carnitine. The resulting acyl carnitine crosses the inner mitochondrial membrane.
CAT-I is associated with the outer mitochondrial membrane.
CAT-I reaction is rate-limiting;
The enzyme is allosterically inhibited by malonyl CoA. Malonyl CoA concentration would be high during fatty acid synthesis. Inhibition of CAT-I by malonyl CoA prevents simultaneous synthesis and degradation of fatty acids.
If there is a double bond at an odd-numbered carbon (e.g., 18:1 9 ), the action of enoyl CoA isomerase is required to move the naturally occurring cis- bond and convert it to the trans- bond used in beta-oxidation.
The product, with a trans- double bond, is a substrate for enoyl CoA hydratase, the second enzyme of beta-oxidation.
These are the compounds known as ketone bodies. Notice that beta-hydroxybutyrate is not chemically a ketone. It is considered to be physiologically equivalent to one because beta hydroxybutyrate and acetoacetate are readily interconverted in the body.
When there is a condition of high rate of fatty acid oxidation, large amounts of acetyl CoA are formed which exceed the oxidative capacity of liver and then liver produces large amounts of compounds ( organic acids ) like acetoacetate and beta hydroxy butyric acid , which pass into blood and then to peripheral tissues where they can be utilized.
Ketone body production is regulated primarily by availability of acetyl CoA. If mobilization of fatty acids from adipose tissue is high, hepatic beta-oxidation will occur at a high rate, and so will synthesis of ketone bodies from the resulting acetyl CoA. The rate of ketone body production increases in starvation.
In the second step, a third molecule of acetyl CoA condenses with the acetoacetyl CoA, forming 3-hydroxy-3-methylglutaryl CoA (HMG CoA) in a reaction catalyzed by HMG CoA synthase… present only in liver.
HMG CoA Synthase is the rate limiting enzyme for ketogenesis.
In the third step HMG CoA is cleaved to yield acetoacetate (a ketone body) in a reaction catalyzed by HMG CoA lyase (HMG CoA cleavage enzyme)… present only in liver. One molecule of acetyl CoA is also produced.
Acetoacetate can be reduced to beta-hydroxybutyrate by beta-hydroxybutyrate dehydrogenase in a NADH-requiring reaction. The extent of this reaction depends on the state of the NAD pool of the cell; when it is highly reduced, most or all of the ketones can be in the form of beta-hydroxybutyrate.
Ketoacidosis …. Acetoacetic acid and beta hydroxy butyric acid are moderately strong acids. When their synthesis exceeds their utilization, their amount exceeds in blood and tissues. They need to be buffered. There can be progressive loss of buffer cations and this results in ketoacidosis.
Cholesterol synthesis has to be tightly regulated as the imbalance between synthesis/intake and utilization leads to accumulation of cholesterol in blood vessels which have serious consequences ---- atherosclerosis.
HMGCoA reductase is the rate limiting enzyme and it is the major control point for cholesterol synthesis.
If the cholesterol in the cell derived from the lipoproteins is not immediately used for structural and synthetic purposes, it is converted into esterified form and then stored in the cell. Enzyme for this esterification is Acyl CoA-cholesterol acyltransferase ( ACAT ). Activity of ACAT is increased by free cholesterol.
HDL transfers cholesterol esters to other lipoproteins and also carries cholesterol to liver for bile acid synthesis , excretion via bile and hormone synthesis. This is called “Reverse cholesterol transport”. Uptake of HDL2 by liver takes place through SR-B1 receptors.