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.
QuickTime™ and a
decompressor
are needed to see this picture.
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).
QuickTime™ and a
decompressor
are needed to see this picture.
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 own 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.
QuickTime™ and a
decompressor
are needed to see this picture.
An alternative representation:
QuickTime™ and a
decompressor
are needed to see this picture.