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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
C14 – C20
>C20
short-chain FA (SCFA)
medium-chain FA (MCFA)
long-chain FA (LCFA)
very-long-chain FA (VLCFA)
Overview of FA
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
Acetyl-CoA 1.
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
Precursors for FA biosynthesis
Acetyl-CoA
+ HSCoA
OAA - oxaloacetate
Formation of malonyl-CoA catalysed by acetyl-CoA-carboxylase (ACC)
HCO3- + ATP ADP + Pi
enzyme-biotin enzyme-biotin-COO-
enzyme-biotin
acetyl-CoA
malonyl-CoA
+
1 carboxylation of biotin 2 transfer of carboxyl group to acetyl-CoA
formation of malonyl-CoA
enzyme – acetyl-CoA-carboxylase
FA biosynthesis
repeated extension of FA by two carbons in each cycle
on the multienzyme complex – FA synthase
to the chain length C16 (palmitate)
FA biosynthesis
ACP – acyl carrier protein
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
+
palmitate
thioesterase
FA biosynthesis
H2O
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 system 1.
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 system 2.
in mitochondria
acetyl-CoA – the donor of the C2 unit
NADPH + H+ – the donor of the reducing equivalents
FA biosynthesis
fatty acid synthase
FA desaturation
in the endoplasmic reticulum
process requiring O2, NADH, cytochrome b5
FA biosynthesis
enzymes: desaturase, NADH-cyt b5-reductase
4 desaturases:
double bonds at position 4,5,6,9
linoleic, linolenic – essential FA
stearoyl-CoA + NADH + H+ + O2 oleoyl-CoA + NAD+ + 2H2O
FA biosynthesis - summary
• Formation of malonyl-CoA • Acetyl-CoA-carboxylase
• FA synthesis
Palmitic acid • FA Synthase– cytosol
Saturated fatty acids(>C16) Elongation systems- mitochondria, ER
Unsaturated fatty acids Desaturation system - ER
-
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
1 2
3
4
5 In the liver , acetyl CoA is converted to ketone bodies
FA degradation
http://che1.lf1.cuni.cz/html/Odbouravani_MK_3sm.pdf
C10 , C12 Branched FA VLCFA
-carbon β-carbon -carbon
-oxidation β-oxidation -oxidation
mainly in muscles
localization: mitochondrial matrix
peroxisome (VLCFA)
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 LCFA into mitochondrion
FA transfer across the inner mitochondrial membrane by 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
Carnitine
FA degradation
3-hydroxy-4-N-trimethylaminobutyrate Sources: Exogenous: meat, dairy products Endogenous: synthesis from lysine and methionine Transported into the cell by specific transporter Deficiency: Decreased transport of acyl-CoA into mitochondria lipids accumulation myocardial damage muscle weakness Increased utilization of Glc hypoglycemia
Similar symptoms are the genetically determined deficiency carnitinpalmitoyltransferase I or II
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 FAD creation of unsaturated acid
hydration
addition of water on the β-carbon atom creation of β-hydroxyacid
dehydrogenation
oxidation by NAD+
creation of β-oxoacid
cleavage at the presence of CoA
formation of acetyl-CoA formation of acyl-CoA (two carbons shorter)
β-oxidation
-dehydrogenase
FA degradation
http://che1.lf1.cuni.cz/html/Odbouravani_MK_3sm.pdf
FA degradation
Oxidation of unsaturated FA
3 rounds of β-oxidation
Normal intermediates of β-oxidation
β-oxidation of oleic acids 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
oleic acid, linoleic acid
intramolecular transfer of double bond
from β- to - β position
Unsaturated FA are cis isomers - aren´t
substrate for enoyl-coA hydratase
continuation of β-oxidation
Oxidation of odd-chain FA
propionyl-CoA
methylmalonyl-CoA
succinyl-CoA
HCO3- + ATP
ADP + Pi
propionyl-CoA carboxylase
(biotin)
methylmalonyl-CoA mutase
(B12)
shortening of FA to C5
formation of acetyl-CoA and propionyl-CoA
carboxylation of propionyl-CoA
intramolecular rearrangement to form succinyl-CoA
entry of succinyl-CoA into the citric acid cycle
stopping of β-oxidation
FA degradation
Peroxisomal oxidation of VLCFA
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 acids
of phospholipids
Peroxisomal oxidation of VLCFA
FA degradation
In peroxisome shortened FA bind to carnitine acylcarnitine
transfer acylcarnitine into mitochondrion β-oxidation
Oxidation carbon
ER liver, kidney
Substrates C10 a C12 FA
Products: dicarboxylic acids
FA degradation
- oxidation
Excreted in the urine
mixed function oxidase
Comparison of FA biosynthesis and FA degradation
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
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
medium strength acids - ketoacidosis
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
http://www.hindawi.com/journals/jobes/2011/482021/fig2/
Marks, A.; Lieberman, M. Marks' basic medical biochemistry: a clinical approach.
3rd edition. Lippincott Williams & Wilkins, 2009.
Meisenberg, G.; Simmons, W. H. Principles of medical biochemistry. 2nd edition.
Elsevier, 2006.
Matouš a kol. Základy lékařské chemie a biochemie. Galén, 2010.
Devlin, T. M. Textbook of biochemistry: with clinical correlations. 6th edition.
Wiley-Liss, 2006.
Murray et al. Harper's Biochemistry. 25th edition. Appleton & Lange, 2000.
Bibliography and sources