Icm 2219 Synthesis of Triacylglycerols
Icm 2219 Synthesis of Triacylglycerols
Icm 2219 Synthesis of Triacylglycerols
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.
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.
Steps involved:
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ICM 2219: LIPID METABOLISM Lecturer: Ms. Wamae
TRIGLYCERIDE SYNTHESIS, GLYOXYLATE CYCLE
Credit:
https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/glyoxylate-cycle
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ICM 2219: LIPID METABOLISM Lecturer: Ms. Wamae
TRIGLYCERIDE SYNTHESIS, GLYOXYLATE CYCLE
*Two molecules of acetyl-CoA enter into each glyoxylate cycle and produce one molecule of
succinate, which is then available for biosynthetic purposes.
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