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Icm 2219 Synthesis of Triacylglycerols

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ICM 2219: LIPID METABOLISM Lecturer: Ms.

Wamae
TRIGLYCERIDE SYNTHESIS, GLYOXYLATE CYCLE

SYNTHESIS OF TRIACYLGLYCEROLS
Liver and adipose tissue are the major sites of triacylglycerol (TAG) synthesis. The TAG synthesis in
adipose tissue is for storage of energy whereas in liver it is mainly secreted as VLDL and is
transported.
The TAG is synthesized by esterification of fatty acyl CoA with either glycerol-3-phosphate or
dihydroxy acetone phosphate (DHAP). The glycerol part of the fat is derived from the metabolism of
glucose. DHAP is an intermediate of glycolysis.
Glycerol-3-phosphate may be formed by phosphorylation of glycerol or by reduction of
dihydroxyacetone phosphate (DHAP).
In adipose tissue, glycerol kinase is deficient and the major source is DHAP derived from
glycolysis.
However in liver, glycerol kinase is active. The fatty acyl CoA molecules transfer the fatty acid to the
hydroxyl groups of glycerol by specific acyl transferases.

In addition to these two pathways, in the intestinal mucosal cells the TAG synthesis occurs by the
MAG pathway. The 2-MAG absorbed is re-esterified with fatty acyl CoA to form TAG.
Esterification of fatty acyl CoA with glycerol phosphate to form triacyl glycerol occurs at a rapid rate
during the fed state.
Under conditions of fasting, it is seen that synthesis of triacyl glycerol occurs side by side with
lipolysis, since the free fatty acid level is high in plasma. The glycerol phosphate is derived from the
metabolism of glucose in the fed state by channeling dihydroxy acetone phosphate, an intermediate of
glycolysis. In the fasting state, the glycerol phosphate is derived from dihydroxy acetone phosphate
formed during gluconeogenesis (neoglycerogenesis). The activity of the enzyme PEPCK is enhanced
in liver and
adipose tissue during conditions of fasting, so that glycerol phosphate is available to esterify and store
the excess fatty acid mobilized.

Substrates required for synthesis of TG are:


• α-Glycero-P (sn-glycerol-3-P) and
• FA (Acyl-CoA)
Sources of α-Glycero-P
• α-Glycero-P is formed from glycerol by the action of the enzyme glycerokinase in presence of ATP.

Tissues which possess the enzyme can form α-Glycero-P. Glycerokinase enzyme is absent or very
low in activity in muscle and adipose tissue.
• Alternative source of α-Glycero-P in tissues like muscle/adipose tissue, where glycerokinase is
lacking is derived from an intermediate of the glycolytic system, dihydroxyacetone-P. α-Glycero-P is
formed from dihydroxy-acetone-P by reduction with NADH catalysed by the enzyme Glycerol-3-
Pdehydrogenase.

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ICM 2219: LIPID METABOLISM Lecturer: Ms. Wamae
TRIGLYCERIDE SYNTHESIS, GLYOXYLATE CYCLE

Steps of Synthesis
1. Fatty acids are activated by Acyl-CoA synthetase to form acyl-CoA in presence of ATP and CoA-
SH.
2. Two molecules of acyl-CoA then combine with α-Glycero-P to form Phosphatidic acid (1,2-diacyl
glycerol-P).
This takes place in two stages:
• First Lysophosphatidic acid is formed, the reaction is catalysed by the enzyme Glycerol-3-P-acyl
transferase.
• Next, phosphatidic acid is formed by the enzyme 1-acyl glycerol-3-P-acyl transferase
(lysophosphatidate
acyl transferase).
3. Phosphatidic acid is now converted to 1,2-diacylglycerol by the enzyme phosphatidate
phosphohydrolase.
4. A further molecule of acyl-CoA is esterified with the diacyl glycerol to form one molecule of tri-
acyl glycerol (TG). The reaction is catalysed by the enzyme diacylglycerol acyltransferase.
Site of Synthesis
1. Most of the activity of these enzymes resides in endoplasmic reticulum of the cell, but some is
found in mitochondria, e.g. Glycerol-3-P-acyl transferase.
2. Phosphatidate Posphohydrolase activity is found mainly in the particle-free supernatant fraction
but also is membrane bound.
Note: Monoacyl glycerol pathway: In intestinal mucosa,a monoacyl glycerol pathway exists,
whereby monoacylglycerol can be directly converted to “diacyl glycerol” as a result of the presence of
the enzyme monoacylglycerol acyltransferase.

GLYOXYLATE REACTION CYCLE


This is a special variant of the tricarboxylic cycle (TCA) that allows utilization of two carbons
compounds in the absence of glucose. The glyoxylate cycle is generally not present in human and
animal tissue, and can only be found in plants, bacteria, fungi and protists (Chew et al., 2019c)
Hans Kornberg and Neil Madsen elucidated this pathway in the laboratory of Hans Krebs.
The enzymes of the gyloxylate cycle catalyze the net conversion of acetate to succinate or other four
carbon intermediates of the citric acid cycle.
Vertebrates (including man) cannot convert fatty acids, or the acetate derived from them, to
carbohydrates since they lack enzymes of the glyoxylate cycle.
Location: glyoxysomes found in peroxisomes.
Common enzymes: Citrate synthase, Isocitrate lyase and Malate dehydrogenase
Key enzymes: Isocitrate lyase and Malate synthase
Compartments: glyososome, mitochondria
The glyoxylate cycle enables acetyl-CoA to be converted into malate. The glyoxylate cycle occurs in
the peroxisomes and converts the acetyl-CoA produced by ß-oxidation of fatty acids into succinate.
Then, succinate is converted in malate through the TCA cycle.

Steps involved:

 Glyoxylate cycle is regarded as an anabolic variant of citric acid cycle.


 It has two unique enzymes; isocitrate lyase and malate synthase which bypass some of the
reactions of TCA cycle.

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ICM 2219: LIPID METABOLISM Lecturer: Ms. Wamae
TRIGLYCERIDE SYNTHESIS, GLYOXYLATE CYCLE

 The glyoxylate cycle involves the following steps:

Credit:
https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/glyoxylate-cycle

1. Condensation of acetyl-CoA with oxaloacetate to form citrate:


 Acetyl-CoA produced either from acetate or by β-oxidation of fatty acids enters into
TCA cycle and is condensed with oxaloacetate to form citrate.
2. Isomerization of citrate to isocitrate:
 Citrate is isomerized to isocitrate in TCA cycle.
3. Cleavage of isocitrate to from succinate and glyoxylate:
 This is the bypass reaction of TCA cycle.
 Unlike the breakdown of isocitrate by isocitrate dehydrogenase in TCA cycle, here,
isocitrate is cleaved by isocitrate lyase to form succinate and glyoxylate.
4. Condensation of glyoxylate with acetyl-CoA to yield malate:
 Succinate is further metabolized by TCA cycle.
 Glyoxylate then condenses with a second molecule of acetyl-CoA to form malate
catalyzed by malate synthase.
5. Oxidation of malate to form oxaloacetate:

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ICM 2219: LIPID METABOLISM Lecturer: Ms. Wamae
TRIGLYCERIDE SYNTHESIS, GLYOXYLATE CYCLE

 Malate is oxidized subsequently to oxaloacetate by the enzyme malate dehydrogenase.


 Oxaloacetate then starts another turn of the cycle.

*Two molecules of acetyl-CoA enter into each glyoxylate cycle and produce one molecule of
succinate, which is then available for biosynthetic purposes.

Significance of Glyoxylate cycle:

 It is a bypass reaction of TCA cycle.


 Oxaloacetate formed in this pathway can be used to synthesize glucose via gluconeogenesis.
 It occurs in bacteria when they are cultured in acetate rich carbon source (acetate being the
sole source of carbon).
 This pathway is very significant in germinating seeds where the stored triacylglycerols (fat) is
converted into sugars to meet the energy needs.
 When higher fatty acids are oxidized into acetyl-CoA without forming pyruvates, then acetyl-
CoA enters into glyoxylate cycle.

Pathway regulation:
Regulation of isocitrate dehydrogenase activity determines the partitioning of isocitrate between the
glyoxylate and citric acid cycles.
When the enzyme is inactivated by phosphorylation (by a specific protein kinase), isocitrate into
biosynthetic reactions via glyoxylate cycle.
When the enzyme is activated by dephosphorylation (by a specific phosphatase), isocitrate enters the
TCA cycle and ATP is produced.

Reference

1. Lehninger, A. L., Nelson, D. L., & Cox, M. M. (2000). Lehninger principles of biochemistry.
New York: Worth Publishers
2. Shindee, R., and Chartajjea, M. (2012).Textbook of Medical Biochemistry 8th Edition, Jaypee
Brothers Medical Publishers (P) LTD. Page 533

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