Acetyl-CoA carboxylase in photosynthetic tissue - Massey University
Metabolism of acylglycerols and...
Transcript of Metabolism of acylglycerols and...
Metabolism of acylglycerols
and sphingolipids
Martina Srbová
Types of glycerolipids and sphingolipids
1. Triacylglycerols
function as energy reserves
adipose tissue (storage of triacylglycerol), lipoproteins
Lipogenesis - the synthesis of triacylglycerols from glucose (mainly in the liver)
Synthesis of TG
in the smooth endoplasmic reticulum
The sources of glycerol 3-phosphate:
1. the phosphorylation of glycerol (glycerol kinase)
liver
2. the reduction of dihydroxyacetone phosphate
(from glycolysis)
liver, adipose tissue
Phosphatidic acid
- the precursor for:
1. TG
2. glycerophospholipids
Dephosphorylation:
Addition of another acyl:
Formation of TG:
Synthesis, processing and
secretion of VLDL
proteins synthesized on the rough
ER are packaged with TG in the ER
and GC to form VLDL
TG, cholesterol, phospholipids and
proteins
VLDL
Fate of VLDL TG
Lipoprotein lipase
present on the lining cells of the capillaries (in adipose and sceletal muscle tissue)
coenzyme Apo C-II (from HDL)
hydrolyses TG from VLDL and chylomicrons
Storage of TG in adipose tissue
Insulin
glucose transport into cells
synthesis and secretion of LPL
Release of FA from adipose TG
↓Insulin, ↑Glucagon
intracellular cAMP increases - activates protein kinase A - phosphorylates
hormone-sensitive lipase
FA - complexes with albumin, oxidized to CO2 and water in tissues
Prolonged fasting - ketone bodies (from acetyl CoA), gluconeogenese (glycerol)
2. Glycerophospholipids
the major lipid components of biological membranes
lipoproteins, bile, lung surfactant
source of PUFA (eicosanoids)
signal transmission (hydrolysis of PIP2)
Sythesis of glycerophospholipids
Precursor: Phosphatidic acid
2 mechanisms of addition of a head group
Phosphatidic acid
2. Phospholipid interconversions:
Synthesis of glycerophospholipids
1. Phosphatidic acid - addition of a head group to the
molecule
Phospholipases
located in cell membranes or in lysosomes
Phospholipase A2 Phospholipase C
Arachidonic acid - eicosanoids Hydrolysis of PIP2 - the second messengers
Repair mechanism for membrane DAG and IP3
lipids damaged by free radicals
Degradation of glycerophospholipids
3a. Sphingomyelins
membrane components (make up 10-20% of plasma membrane lipids)
myelin
Sphingosine
3. Sphingolipids
3b. Glycolipids
the surfaces of cell membranes, receptors (hormons, cholera toxin),
specific determinats of cell-cell recognition, the antigenic determinants
of the ABO blood groups
cerebrosides, sulfatides, gangliosides
Synthesis of sphingolipids
In the Golgi complex
Formation of ceramide:
Precursors:
Serine + Palmitoyl CoA condense
to form the sphingosine
FA forms an amide with amino
group - ceramide
Degradation of sphingolipids
by lysosomal enzymes (deficienties result in lysosomal storage disease =
sphingolipidoses)
Sphingolipidoses
genetic mutations, mental retardation, death
Nemoc Deficit enzymu Kumulující lipid
Fucosidosis α-Fucosidase H-Isoantigen
Generalized gangliosidosis GM1-β-Galactosidase GM1-Ganglioside
Tay-Sachs disease Hexosaminidase A GM2-Ganglioside
Tay-Sachs variant Hexosaminid. A and B GM2-Ganglioside
Fabry disease α-Galactosidase Globotriaosylceramide
Ceramide lactoside lipidosis Ceramide lactosidase Ceramide laktoside
Metachromatic leukodystrophy Arylsulfatase A 3-Sulfogalactosylceramide
Krabbe disease β-Galactosidase Galactosylceramide
Gaucher disease β-Glucosidase Glucosylceramide
Niemann-Pick disease Sphingomyelinase Sphingomyelin
Farber disease Ceramidase Ceramide
Tay-Sachs disease
ganglioside accumulation in neurons
Regulation of lipid metabolism
Control of fatty acid synthesis
• Regulation at the level of Acetyl-CoA Carboxylase
ACC is regulated by
phosphorylation
allosteric control by local metabolites
diet: high caloric diet stimulates ACC synthesis - long term reg.
• Regulation at the level of Fatty Acid Synthase
– transcriptionally regulated
Insulin stimulates Fatty Acid Synthase expression.
Leptin inhibits Fatty Acid Synthase expression.
short-term reg.
Acetyl-CoA Carboxylase, which converts acetyl-CoA to malonyl-CoA, is the rate-limiting step of the fatty acid synthesis pathway.
The Acetyl-CoA Carboxylase is regulated by
phosphorylation
allosteric control by local metabolites.
Conformational changes associated with regulation:
In the active conformation, Acetyl-CoA Carboxylase associates to form multimeric filamentous complexes.
Transition to the inactive conformation is associated with dissociation to yield the monomeric form of the enzyme (protomer).
Control of fatty acid synthesis
Regulation at the level of ACC
Control of fatty acid synthesis
Adrenalin
Glucagon cAMP
Protein
kinase A -
AMP-Activated Kinase, a sensor of cellular energy levels, is allosterically activated by AMP, which is high in concentration when [ATP] is low.
Acetyl-CoA Carboxylase is inhibited when phosphorylated by AMP- activated kinase, leading to decreased malonyl-CoA
The decreased production of malonyl-CoA prevents energy-utilizing fatty acid synthesis when cellular energy stores are depleted.
Regulation at the level of ACC
Control of fatty acid synthesis
Adrenalin
Glucagon cAMP
Protein
kinase A -
A cAMP cascade, activated by glucagon & adrenaline when blood glucose is low, may also result in phosphorylation of Acetyl-CoA Carboxylase via Protein Kinase A.
With Acetyl-CoA Carboxylase inhibited, acetyl-CoA remains available for synthesis of ketone bodies, the alternative metabolic fuel used when blood glucose is low.
The antagonistic effect of insulin, produced when blood glucose is high, is attributed to activation of Protein Phosphatase.
Regulation at the level of ACC
Control of fatty acid synthesis
Adrenalin
Glucagon cAMP
Protein
kinase A -
Palmitoyl-CoA (product of Fatty Acid Synthase) promotes the inactive conformation, diminishing production of malonyl-CoA, the precursor of fatty acid synthesis.
This is an example of feedback inhibition.
Citrate allosterically activates Acetyl-CoA Carboxylase
[Citrate] is high when there is adequate acetyl-CoA entering Krebs Cycle.
Excess acetyl-CoA is then converted via malonyl-CoA to fatty acids for storage
Control of fatty acid degradation
1. PPAR peroxisome proliferator activated receptor
2. Energy demands of cell
3. Carnitine palmitoyl transferase I (CPT I)
Control of fatty acid degradation
1. PPAR peroxisome proliferator activated receptor
nuclear receptors act as transcription factors role in regulating the storage and degradation of dietary lipids
After binding of the ligand to receptor, these bind to DNA and initiate
transcription of genes whose products participate in β-oxidation
Ligands for PPARs:
regulate the cellular uptake of FA
activation of FA
-oxidation of FA
fatty acids C >12 , mainly 3 PUFA fibrate (drug acts on dyslipidemia)
Regulation of β-oxidation
acetyl-CoA malonyl-CoA CPT I β-oxidation
ACC
2. by energy demands of cell by the level of ATP and NADH:
FA can not be oxidized faster than NADH and FADH2 are reoxidized in the respiratory chain
3. via carnitine palmitoyl transferase I (CPT I)
CPT I is inhibited by malonyl-CoA, which is generated in the synthesis of FA by acetyl-CoA carboxylase
(ACC)
active FA synthesis inhibition of β-oxidation
Control of fatty acid degradation
Adipose tissue as an endocrine organ
Leptin
• Protein, released from
adipocytes as their TG levels
increase
• Binds to the receptors in the
hypothalamus, which leads to
the release of neuropeptides
that signal suppress appetite
• In the muscle and liver, it
stimulates FA oxidation
Adiponectin
• ↑FA oxidation by the liver and
muscle
• ↑Uptake and utilization of glucose
by the muscle
• ↓Hepatic glucose production
glucagon
epinephrine
insulin
glucagon
epinephrine
inhibition by
dephosphorylation insulin
carnitine palmitoyl
transferase I
inhibited by
phosphorylation by
AMP-activated kinase
FA metabolism is dependent upon the ratio of insulin to glucagon.
FA degradation: low insulin / glucagon ratio
FA synthesis: high insulin / glucagon ratio x
Insulin Glucagon
Activity:
Acetyl –CoA-carboxylase + - Hormone-sensitive lipase - + Synthesis:
Acetyl –CoA-carboxylase + - FA synthase + - Lipoprotein lipase + -
+ activation
- inhibition
Pictures used in the presentation:
Marks´ Basic Medical Biochemistry, A Clinical Approach, third edition, 2009 (M.
Lieberman, A.D. Marks)
Color Atlas of Biochemistry, second edition, 2005 (J. Koolman and K.H. Roehm)
Devlin, T. M. Textbook of biochemistry: with clinical correlations. 6th edition. Wiley-Liss,
2006.
Biochemistry, Voet and Voet, 4th edition 2011