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Pathways of Carbohydrate & Lipid Metabolism (Part II)

5. Describe how fatty acid is mobilised from adipose tissue stores and transported to the liver for subsequent oxidation

Adipose tissue triglycerides are derived form two sources: dietary lipids and liver-synthesised trigylcerides. The major fatty acids (FA) oxidized are longchain: palmitate, oleate, stearate, which are the most common dietary FA, and are also synthesized in humans. During fasting, and conditions of metabolic need, long-chain FA are released from adipose tissue triglycerides by glucagon-activated lipases. These hormone-sensitive lipases, also known as adipose triglycerol lipase, cleaves a FA from a triglyceride and free FA are transported to liver tissues & muscle bound to serum albumin in the blood.

Here they are oxidized to Co2 & H2O to produce energy. The glycerol derived form lipolysis in adipose cells is used by the liver during fasting as a source of carbon for gluconeogenesis.

FA enter cells by a saturable transport process and by diffusion through the lipid plasma membrane. A FA-binding protein in the membrane facilitates transport. An additional FA-binding protein binds to the FA intracellularly, and transports it to the mitochondria. Here the FA are activated to acyl-derivatives before they can participate in B-oxidation (like phosphorylation of glucose to

G6P), a process that involves acyl CoA synthetase at the mitochondrial membrane or endoplasmic reticulum.

6. Outline the pathway of beta-oxidation, including the carnitine acyl carrier system and the substrates and products of the pathway

Within cells, energy is derived from fats by oxidation from FA to Acetyl-CoA in the B-oxidation pathway. Carnitine is the carrier that transports activated fattyacyl groups across the mitochondrial membrane. Carnitine acyl transferases are able to reversibly transfer an activated fatty acyl group from CoA to the hydroxyl group of carnitine to from an acylcarnitine ester.

Carnitine:palmitoyltransferase I (CPTI), the enzyme that transfers fatty-acyl groups from CoA to carnitine, is located on the mitochondrial membrane.

Fatty acylcarnitine crosses the inner mitochondrial membrane with the aid of a translocase. The fatty-acyl group is transferred back to CoA by a second enzyme (CTPII). Hence the long-chain fatty-acyl CoA, now located within the mitochondrial membrane, is a substrate for B-oxidation.

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The FA B-oxidation pathway sequentially cleaves the fatty-acyl group into two-carbon acetyl CoA units. Before cleavage, the B-carbon is oxidized to a keto group in two reactions that generate NADH and FAD(2H) – thus the pathway is called B-oxidation. There are four types of reactions in the Boxidation pathway:

1) A double bond is formed between the B- & a-carbons by an acyl CoA dehydrogenase that transfers electrons to FAD

2) An –OH from water is added to the B-carbon, and an –H from water to the a-carbon. The enzyme is called enoyl hydratase

3) The –OH group on the B-carbon is oxidized to a ketone by a hydroxyacyl CoA dehydrogenase enzyme

4) The bond between the B- & a-carbons is cleaved, releasing acetyl

CoA.

The shortened fatty-acyl CoA repeats these four steps until all its carbons are converted to acetyl CoA. Hence B-oxidation is a spiral rather than a cycle.

The acetyl-CoA derived is either further oxidized in the TCA cycle or converted to ketone bodies in the liver. For each 2-carbon fragment removed from the FA, the cell gains 12 ATP molecules from processing in the TCAcycle, plus 5 ATP molecules from the NADH & FAD(2H).

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7. Draw a diagram showing how the pathways of glycolysis, betaoxidation, citric acid cycle and gluconeogenesis interact, showing common intermediates and the cellular compartmentation of the pathways

The below figure illustrates in summary from the interconnected nature the pathways of glycolysis, B-oxidation, TCA-cycle and gluconeogenesis. This represents a ‘typical’ cell, though no one cell can perform all the anabolic and catabolic operations and interconversions required by the body. Each cell develops its ow n complement of enzymes that determines the cell’s metabolic activities.

Key common intermediates are pyruvate, acteyl-CoA, with the irreversible conversion of pyruvate to acteyl-CoA being important in regulating reactions.

The TCA-cycle, B-oxidation and the electron transport chain all process in the mitochondria or mitochondrial membrane, whilst other key reactions occur within cell cytostol.

An alternative representation:

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