Synthesis and degradation of fatty acids
description
Transcript of Synthesis and degradation of fatty acids
Synthesis and degradation of fatty acids
Zdeňka Klusáčková
Fatty acids (FA)
mostly an even number of carbon atoms and linear chain
in esterified form as component of lipids
in unesterified form in plasma binding to albumin
Groups of FA:
according to the number of double bonds
no double bond
one double bond
more double bonds
saturated FA (SAFA)
monounsaturated FA (MUFA)
polyunsaturated FA (PUFA)
according to the chain length
<C6
C6 – C12
C12 – C20
>C20
short-chain FA (SCFA)
medium-chain FA (MCFA)
long-chain FA (LCFA)
very-long-chain FA (VLCFA)
Overview of FA
Triacylglycerols
main storage form of FA
acylglycerols with three acyl groups
stored mainly in adipose tissue
function: energy storage in the form of TAG
acyl-CoA and glycerol-3-phosphate
TAG incorporation into very low density lipoproteins (VLDL)
entry of VLDL into the blood circulation
TAG transport from the liver to other tissues via VLDL
synthesis of TAG in liver
(especially skeletal muscle, adipose tissue)
FA biosynthesis in the excess of energy (increased caloric intake)
FA biosynthesis
mainly in the liver, adipose tissue, mammary gland during lactation
localization: cell cytoplasm (up to C16)
endoplasmic reticulum, mitochondrion
enzymes: acetyl-CoA-carboxylase (HCO3- - source of CO2, biotin, ATP)
fatty acid synthase (NADPH + H+, pantothenic acid)
primary substrate: acetyl-CoA
final product: palmitate
(elongation = chain extension)
(always in excess calories)
FA biosynthesis
repeated extension of FA by two carbons in each cycle
on the multienzyme complex – FA synthase
to the chain length C16 (palmitate)
palmitate, a precursor of saturated and unsaturated FA:
saturated FA (> C16) elongation systems
unsaturated FA desaturation systems
FA biosynthesis
Acetyl-CoA1.
source: oxidative decarboxylation of pyruvate (the main source of glucose)
NADPH 2.
source: pentose phosphate pathway (the main source)
the conversion of malate to pyruvate (NADP+-dependent malate dehydrogenase - „malic enzyme”)
transport across the inner mitochondrial membrane as citrate
the conversion of isocitrate to α-ketoglutarate (isocitrate dehydrogenase)
degradation of FA, ketones, ketogenic amino acids
Precursors for FA biosynthesis
Formation of malonyl-CoA
HCO3- + ATP ADP + Pi
enzyme-biotin enzyme-biotin-COO-
enzyme-biotin
acetyl-CoA
malonyl-CoA
biotinyl-enzyme carboxybiotinyl-enzyme
+
1 carboxylation of biotin 2 transfer of carboxyl group to acetyl-CoA
formation of malonyl-CoA
enzyme – acetyl-CoA-carboxylase
FA biosynthesis
Regulation at the level of ACC
acetyl-CoA malonyl-CoA palmitateglucose citrate palmitoyl-CoA
acetyl-CoA carboxylase
protein kinase A AMP-dependent
insulin AMPcAMP
glucagon adrenaline
FA biosynthesis
protein kinase A
FA synthase
FA biosynthesis
FA biosynthesis
The course of FA biosynthesis
acetyl-CoA malonyl-CoA
acetyltransacylase
acyl(acetyl)-malonyl-
CoASH CoASH
transacylation
-enzyme complex
malonyltransacylase
acyl(acetyl)-malonyl-enzyme complex 3-ketoacyl-enzyme complex
3-ketoacyl-synthase
CO2
condensation
(acetacetyl-enzyme complex)
FA biosynthesis
The course of FA biosynthesis
3-ketoacyl-enzyme complex(acetoacetyl-enzyme complex)
3-hydroxyacyl-enzyme complex
NADPH + H+ NADP+
3-ketoacyl-reductase
H2O
3-hydroxyacyl- dehydrase
2,3-unsaturated acyl-enzyme complex acyl-enzyme complex
NADPH + H+ NADP+
enoylreductase
first reduction dehydration second reduction
FA biosynthesis
The course of FA biosynthesis
Repetition of the cycle
acyl-enzyme complex(palmitoyl-enzyme complex)
CoASH
malonyl-CoA
FA biosynthesis
The release of palmitate
palmitoyl-enzyme complex
H2O
+
palmitate
thioesterase
FA biosynthesis
The fate of palmitate after FA biosynthesis
palmitate palmitoyl-CoA
acylglycerols
cholesterol esters
acyl-CoA
esterification
elongation
desaturation
acyl-CoA-synthetase
ATP + CoA AMP + PPi
FA biosynthesis
FA elongation
microsomal elongation system1.
in the endoplasmic reticulum
malonyl-CoA – the donor of the C2 units
extension of saturated and unsaturated FA
palmitic acid (C16) FA > C16 elongases (chain elongation)
mitochondrial elongation system2.
in mitochondria
acetyl-CoA – the donor of the C2 unit
NADPH + H+ – the donor of the reducing equivalents
not reverse β-oxidation
FA biosynthesis
fatty acid synthase
Microsomal extension of FA
acetyl-CoA malonyl-CoA 3-ketoacyl-CoA
3-hydroxyacyl-CoA 2,3-unsaturated acyl-CoA acyl-CoA
CoASH + CO2
NADPH + H+ NADP+ H2O NADPH + H+ NADP+
+
synthase
reductase hydratase reductase
CoASH + CO2
+
NADPH + H+ NADP+
H2ONADPH + H+ NADP+
palmitoyl-CoA malonyl-CoA
stearoyl-CoA
Example:
FA biosynthesis
FA desaturation
in the endoplasmic reticulum
process requiring O2, NADH, cytochrome b5
FA biosynthesis
FA degradation
function: major energy source
(especially between meals, at night, in increased demand for energy intake – exercise)
release of FA from triacylglycerols in adipose tissue into the bloodstream
binding of FA to albumin in the bloodstream
transport to tissues
entry of FA into target cells activation to acyl-CoA
transfer of acyl-CoA via carnitine system into mitochondria β-oxidation
Most important FA released from adipose tissue:
palmitic acid
oleic acid
stearic acid
long-chain FA (LCFA, C12 – C20)
unsaturated FA
odd-chain-length FA
very-long-chain FA (VLCFA, > C20)
FA with C10 or C12
long-chain branched-chain FA
mitochondrial β-oxidation
mitochondrial β-oxidation
modified
peroxisomal β-oxidation
peroxisomal α-oxidation
ω-oxidation
FA degradation
Mechanisms of FA degradation
α-oxidation ω-oxidation
β-oxidation
Mechanisms of FA degradation
FA degradation
mainly in muscles
localization: mitochondrial matrix
peroxisome
enzymes: acyl CoA synthetase
carnitine palmitoyl transferase I, II; carnitine acylcarnitine translocase
substrate: acyl-CoA
final products: acetyl-CoA
β-oxidation
dehydrogenase (FAD, NAD+), hydratase, thiolase
propionyl-CoA
FA degradation
repeated shortening of FA by two carbons in each cycle
oxidation of acetyl-CoA to CO2 and H2O in the citric acid cycle
generation of 8 molecules of acetyl-CoA from 1 molecule of palmitoyl-CoA
cleavage of two carbon atoms in the form of acetyl-CoA
complete oxidation of FA
PRODUCTION OF LARGE QUANTITY OF ATP
production of NADH, FADH2 reoxidation in the respiratory chain to form ATP
FA degradation
β-oxidation
Activation of FA
fatty acid ATP
pyrophosphate (PPi)
acyl-CoA AMP
acyl-CoA-synthetase
acyl-CoA-synthetase pyrophosphatase
acyl adenylate
fatty acid+ ATP + CoASH acyl-CoA + AMP + PPi
PPi + H2O 2Pi
2Pi
FA degradation
The role of carnitine in the transport of FA into mitochondrion
FA transfer across the inner mitochondrial membraneby carnitine and three enzymes:
carnitine palmitoyl transferase I (CPT I)
acyl transfer to carnitine
carnitine acylcarnitine translocase
acylcarnitine transfer across the inner mitochondrial membrane
carnitine palmitoyl transferase II (CPT II)
acyl transfer from acylcarnitine back to CoA in the mitochondrial matrix
FA degradation
acyl-CoA
trans-Δ2-enoyl-CoA
L-β-hydroxyacyl-CoA
β-ketoacyl-CoA
acyl-CoA acetyl-CoA
acyl-CoA-dehydrogenase
enoyl-CoA-hydratase
L-β-hydroxyacyl-CoA-
β-ketoacyl-CoA-thiolase
Steps of cycle:
dehydrogenation
oxidation by FADcreation of unsaturated acid
hydration
addition of water on the β-carbon atomcreation of β-hydroxyacid
dehydrogenation
oxidation by NAD+
creation of β-oxoacid
cleavage at the presence of CoA
formation of acetyl-CoAformation of acyl-CoA (two carbons shorter)
β-oxidation
-dehydrogenase
FA degradation
Oxidation of unsaturated FA
3 acetyl-CoA3 rounds of β-oxidation
β-oxidation 1 acetyl-CoA
linoleoyl-CoA
NADPH + H+
NADP+
enoyl-CoA-isomerase
enoyl-CoA-isomerase
dienoyl-CoA-reductase
acyl-CoA-dehydrogenase
cis-Δ3, cis-Δ6
trans-Δ2, cis-Δ6
cis-Δ4
trans-Δ2, cis-Δ4
trans-Δ3
trans-Δ2
cis Δ9, cis-Δ12
4 rounds of β-oxidation
5 acetyl-CoA
the most common unsaturated FA in the diet:
degradation of unsaturated FA by β-oxidation to a double bond
conversion of cis-isomer of FA by specific isomerase to trans-isomer
continuation of β-oxidationto the next double bond
oleic acid, linoleic acid
elimination of double bond between C4 and C5 by reduction
formation of double bond between C2 and C3 by dehydrogenation
intramolecular transfer of double bond
continuation of β-oxidation
FA degradation
Oxidation of odd-chain FA
propionyl-CoA
D-methylmalonyl-CoA
L-methylmalonyl-CoA
succinyl-CoA
HCO3- + ATP
ADP + Pi
propionyl-CoA carboxylase (biotin)
methylmalonyl-CoA mutase (B12)
methylmalonyl-CoA racemase
shortening of FA to C5
formation of acetyl-CoA and propionyl-CoA
carboxylation of propionyl-CoA
epimerization of D-form into L-form
intramolecular rearrangement to form succinyl-CoA
entry of succinyl-CoA into the citric acid cycle
stopping of β-oxidation
FA degradation
Peroxisomal oxidation of FA
A) very-long-chain FA (VLCFA, > C20)
Differences between β-oxidation in the mitochondrion and peroxisome:
1. step – dehydrogenation by FAD
mitochondrion: electrons from FADH2 are delivered to the respiratory chain where they are transferred to O2 to form H2O and ATP
peroxisome: electrons from FADH2 are delivered to O2 to form H2O2,
which is degraded by catalase to H2O and O2
3. step – dehydrogenation by NAD+
mitochondrion: reoxidation of NADH in the respiratory chain
peroxisome: reoxidation of NADH is not possible, export to the cytosol or the mitochondrion
transport of acyl-CoA into the peroxisome without carnitine
FA degradation
Differences between β-oxidation in the mitochondrion and peroxisome:
4. step – cleavage at the presence of CoA
mitochondrion: metabolization in the citric acid cycle
peroxisome: export to the cytosol, to the mitochondrion (oxidation)
acetyl-CoA
a precursor for the synthesis of cholesterol and bile acids
a precursor for the synthesis of fatty acidsof phospholipids
Peroxisomal oxidation of FA
FA degradation
B) long-chain branched-chain FA
blocking of β-oxidation by the alcyl group at Cβ
α-oxidation
hydroxylation at Cα
cleavage of the original carboxyl group as CO2
methyl group is in the position α
transfer of FA in the form of acylcarnitine into the mitochondrion
shortening of FA to 8 carbons
complete of β-oxidation in the mitochondrion
Peroxisomal oxidation of FA
FA degradation
Refsum's disease
rare autosomal recessive hereditary disease
phytanic acid a product of metabolism of phytol (part of chlorophyll)
in milk and animal fats
decreased activity of peroxisomal α-hydroxylase accumulation of phytanic acid
(in tissues of nervous system and serum)
ataxia, night blindness, hearing loss, skin changes etc.
ω-oxidation of FA
minor pathway of FA oxidation
in the endoplasmatic reticulum
repeated oxidation of ω-carbon
-CH3 - CH2OH -COOH
formation of dicarboxylic acid
entry of dicarboxylic acid into β-oxidation
reduction of FA to adipic acid (C6) or suberic acid (C8)
excreted in the urine
FA degradation
Regulation of β-oxidation
acetyl-CoA malonyl-CoA CPT I β-oxidation
ACC
A) 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
B) 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
FA degradation
Comparison of FA biosynthesis and FA degradation
in the liver
localization: mitochondrial matrix
substrate: acetyl-CoA
products: acetone
acetoacetate
D-β-hydroxybutyrate
conditions: in excess of acetyl-CoA
function: energy substrates for extrahepatic tissues
Ketone bodies
Ketogenesis
Ketone bodies
Ketogenesis
acetoacetate
spontaneous decarboxylation to acetone
conversion to D-β-hydroxybutyrate by D-β-hydroxybutyrate dehydrogenase
waste product (lung, urine)
energy substrates for extrahepatic tissues
Ketone bodies
Ketogenesis
Utilization of ketone bodies
citric acid cycle
energy source for extrahepatic tissues
(especially heart and skeletal muscle)
in starvation - the main source of energy
energy
production
water-soluble FA equivalents
Ketone bodies
for the brain
Production, utilization and excretion of ketone bodies
acetyl-CoA
oxidation in the citric acid cycle (liver)
conversion to ketone bodies
release of ketone bodies into blood
transport to tissues
Ketone bodies
(liver - mitochondrion)
lipolysis
FA in plasma
β-oxidation
excess of acetyl-CoA
ketogenesis
increased ketogenesis:
starvation
prolonged exercise
diabetes mellitus
high-fat diet
low-carbohydrate diet
utilization of ketone bodies as an energy source
to spare of glucose and muscle proteins
(skeletal muscle, intestinal mucose, adipocytes, brain, heart etc.)
Ketogenesis
Ketone bodies
http://www.hindawi.com/journals/jobes/2011/482021/fig2/
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Matouš a kol. Základy lékařské chemie a biochemie. Galén, 2010.
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Bibliography and sources