biosynthesis of membrane lipids and steroids 1 léránt istván
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Biosynthesis of membrane lipids and steroids 1
Léránt István
BIOSYNTHESIS OF MEMBRANE LIPIDSPhosphatydic acid is a COMMON INTERMEDIER of biosynthesis of
phospholipidsNeutral fats
Biosynthesis of membrane lipids and steroids 1
2
Glycero
l
Fatty acid 1
Fatty acid 2
Fatty acid 3
Glycero
l
Fatty acid 1
Fatty acid 2
P Alcohol
Neutral fats Phospholipids
Glycerol-phosphate acyltransferase
In most tissuesGlycerol / glycerol-kinase
LIver
Adipose tissue:Glycolysis - DHAP
Biosynthesis of membrane lipids and steroids 1
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SYNTHESIS of MEMBRANE LIPIDS and TRIGLYCERIDSPhosphatydic acid is a COMMON INTERMEDIER of biosynthesis of
phospholipidsNeutral fats
ACYL-GLYCEROL-SYNTHETASE COMPLEXENDOPLASMIC RETICULUM
PhosphataseDiacylglycerol acyltransferase
Biosynthesis of membrane lipids and steroids 1
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SYNTHESIS OF MEMBRANE LIPIDSBIOSYNTHESIS OF PHOSPHOLIPIDSACTIVATION OF PHOSPHATIDIC ACID / ALCOHOL
Biosynthesis of membrane lipids and steroids 1
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SYNTHESIS OF PHOSPHATIDYLINOSITOL 4,5 BISPHOSPHATECDP-diacylglycerolPhosphatidyl-inositolPhosphatidyl-inositol4,5 bisphosphate
Biosynthesis of membrane lipids and steroids 1
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Phospholipase C
Cardiolipin - component of the mitochodrial membranes
CH2
C
CH2
O
O
HO
P
O
O
O
CR2
C R1
O
OCH2
C OHH
CH2 O P
O
O
O CH2
C O C
O
R3
CH2OC
O
R4
H
Biosynthesis of membrane lipids and steroids 1
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Phosphatidyl - glycerolPhosphatidyl - glycerol
Diophosphatidyl – glycerol; CardiolipinDiophosphatidyl – glycerol; Cardiolipin
PP-- PP--
pH ~ / = 7,0 pK’ HpH ~ / = 7,0 pK’ H33POPO44 ~ / = 1 - 2 ~ / = 1 - 2
Mitochondria / LuesMitochondria / Lues
Cardiolipin - component of the mitochodrial membranes
Biosynthesis of membrane lipids and steroids 1
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ncardiolipiylglycerolphosphatid
ylglycerolphosphatid(PGP) P-ylglycerolphosphatid
(PGP) P-ylglycerolphosphatideroldiacylglycCDP
eroldiacylglycCDPatephosphatid
atephosphatid P-3-Glycerol
eroldiacylglyc-CDP
ylationdephosphor
synthase PGP
synthaseDAG -CDP
heraseacyltransp phosphate-3-glycerol 2
PP-- PP--CTPCDP
PHOSPHATIDYL-CHOLINECHOLINE:
Food sourcesCirculationPresynaptic cholinergic membraneCholine-transport - high affinity Synthesis of phosphatidyl-choline in hepatocytes from phosphatidyl-ethanolamine
Biosynthesis of membrane lipids and steroids 1
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Choline-kinaseCTP:phosphocholine cytidyliltranspherase
CytoplasmEndoplasmic reticulumEndoplasmic reticulum
Endoplasmic reticulumEndoplasmic reticulum
CDP-CHOLINE: 1,2-diglyceride Phosphocholine ltranspherase
PHOSPHATIDYLETHANOLAMINE&PHOSPHATIDYL-CHOLINELIVER
Biosynthesis of membrane lipids and steroids 1
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CHOLINE
CHOLINE-P
CDP-CHOLINE
PHOSPHATIDYL-CHOLINE
PHOSPHATIDYLSERINE
CO2 3 SAM3 S-adenosyl-homocysteine
PHOSPHATIDYLETHANOLAMINE&PHOSPHATIDYL-CHOLINELIVERRATE LIMITING STEP:CTP:phosphocholine cytidylil-transferase
Cytoplasm – Endoplasmic reticulumTranslocation - activation
+ fatty acid – fatty -acyl-CoA / DAG
cAMP dependent protein kinase
Lipid transport – PCh dependentCholine deficiency / VLDL / fatty liver
Biosynthesis of membrane lipids and steroids 1
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CHOLINE
CHOLINE-P
CDP-CHOLINE
PHOSPHATIDYL-CHOLINE
PHOSPHATIDYLSERINE
CO2 3 SAM3 S-adenosyl-homocysteine
Sphingolipids
Biosynthesis of membrane lipids and steroids 1
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P Choline
X
Sphingomyeline
Glu Glucosyl-cerebroside
Glu GalGal Lactosyl-cerebrozide
GluGlu GalGal GalNAcGalNAc
NeuNAc
GM2 ganglioside
Sphingosine
Fatty ecid
P Choline
Sphingosine
Fatty acid
Glu / Gal
Ceramide
Sphingosine
Fatty acid
X
CH C3
C2
CH2
1
H
OH
H
NH3
+OHCH
szfingozin (4-szfingenin)Sphingosine (4-sphingenene)
Sphingomyelin
CH C3
C2
CH2
1
H
OH
H
NH2
+
O
CH C R
O
P O
O
O
CH2 CH2 N+
CH3
CH3
CH3
Biosynthesis of membrane lipids and steroids 1
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Sphingosine Ceramide Choline Phosphoric acid
Fatty acid
Synthesis of sphigolipids
Biosynthesis of membrane lipids and steroids 1
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sphyngomyeline
GalactocerebrosidesGlucocerebrosides
Gangliosides
Biosynthesis of membrane lipids and steroids 1
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Glucosyl-ceramide / Glucocerebroside
Biosynthesis of membrane lipids and steroids 1
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CeramideCeramideGluGluMonohexosideMonohexoside
CeramideCeramide
GluGluGalGalDihexosideDihexoside CeramideCeramide
GluGluGalGalGalGalTrihexosideTrihexoside
Galactosyl – ceramide / Galactocerebroside
Biosynthesis of membrane lipids and steroids 1
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CeramidCeramidGalGalMonohexosideMonohexoside
GalGalGalGalDihexozidDihexozid CeramidCeramid
ABO blood group system
Biosynthesis of membrane lipids and steroids 1
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Glu GalGal GalNAc Gal
Fuc
Glu GalGal GalNAc Gal
Fuc
Glu GalGal GalNAc Gal
Fuc
Gal
GalNAc
„O” (H) antigen
„A” antigen
„B” antigen
Gangliosides
Biosynthesis of membrane lipids and steroids 1
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CeramideCeramideGluGluGalGal
NANANANA
GGM3M3
CeramideCeramideGluGluGalGal
NANANANA
GalNAcGalNAcGGM2M2
CeramideCeramideGluGluGalGal
NANANANA
GalNAcGalNAcGGM1M1
GalGal
Cholera toxinCholera toxin
Inborn errors of phospholipid, sphingolipid metabolism
• Demyelination: Sclerosis multiplex• White matter decrease of [phospholipid], [plasmenyl
ethanolamine], [sphingolipid]
• Sphingolipidosis:• Accumulation of complex lipids• Synthesis of complex lipids is not effected• Lack of specific (hydrolytic) lysomal enzymes• All tissues are effected
• Multiple sulfatase deficiency
Biosynthesis of membrane lipids and steroids 1
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Sphingolipidoses
• Accumulation of sphingomyelin
Biosynthesis of membrane lipids and steroids 1
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CeramidCeramid P-KolP-KolNiemann-PickNiemann-Pick sphingomyelinase
Gaucher’s - disease
• Accumulation of glucocerebrosides in reticuloendothelial cells of spleen, liver, and bone marrow
• the most common of lysosomal storage disease• Mental retardation
Biosynthesis of membrane lipids and steroids 1
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CeramidCeramid GluGluGaucherGaucher -glukozidáz-glukozidáz
Krabbe disease
• Accumulation of Galactosyl ceramide
Biosynthesis of membrane lipids and steroids 1
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CeramidCeramid GalGalKrabbeKrabbe -galaktosidase
Tay – Sachs Disease
• Deficiency of Hexosaminidase A
• Hexosaminidase A• hydrolyses the N-acetyl-
galactosamine of GM2 ganglioside
• Mental retardation• Macrocephalia• Death at age 2-4• Frequency: Ashkenazi
Jewish population 1:3500
Biosynthesis of membrane lipids and steroids 1
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Tay – Sachs DiseaseTay – Sachs Disease
Biosynthesis of membrane lipids and steroids 1
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CeramidCeramid GluGlu
hexosaminidase
GalGal
NANA
GalNAcGalNAcTay - SachsTay - Sachs
Sphingolipidoses
Biosynthesis of membrane lipids and steroids 1
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CeramideCeramideFabryFabry GluGlu GalGal GalGal
-galactosidase-galactosidase
CHOLESTEROL“Cholesterol is the most highly decorated small molecule in biology. Thirteen Nobel Prizes have been awarded to scientists who devoted major parts of their careers to cholesterol. Ever since it was isolated from gallstones in 1784, cholesterol has exerted an almost hypnotic fascination for scientists from the most diverse areas of science and medicine…. Cholesterol is a Janus-faced molecule. The very property that makes it useful in cell membranes, namely its absolute insolubility in water, also makes it lethal.”
Michael Brown and Joseph GoldsteinNobel Lectures (1985)
Biosynthesis of membrane lipids and steroids 1
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CHOLESTEROL“Cholesterol is the most highly decorated small molecule in biology. Thirteen Nobel Prizes have been awarded to scientists who devoted major parts of their careers to cholesterol. Ever since it was isolated from gallstones in 1784, cholesterol has exerted an almost hypnotic fascination for scientists from the most diverse areas of science and medicine…. Cholesterol is a Janus-faced molecule. The very property that makes it useful in cell membranes, namely its absolute insolubility in water, also makes it lethal.”
Michael Brown and Joseph GoldsteinNobel Lectures (1985)
Biosynthesis of membrane lipids and steroids 1
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CHOLESTEROL“Cholesterol is the most highly decorated small molecule in biology. Thirteen Nobel Prizes have been awarded to scientists who devoted major parts of their careers to cholesterol. Ever since it was isolated from gallstones in 1784, cholesterol has exerted an almost hypnotic fascination for scientists from the most diverse areas of science and medicine…. Cholesterol is a Janus-faced molecule. The very property that makes it useful in cell membranes, namely its absolute insolubility in water, also makes it lethal.”
Michael Brown and Joseph GoldsteinNobel Lectures (1985)
Biosynthesis of membrane lipids and steroids 1
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CHOLESTEROL
• SYNTHESIS OF • Active isoprenoid-units –
isopentenyl-pirophosphate • Acetyl-CoA 3-hydroxy-3-methyl-
glutaryl-CoA (HMG-CoA)– HMG-CoA mevalonate– Mevalonate isopentenyl-PP
• 6 isopentenyl-pyrophosphate squalen
• Cyclisation of squalen cholesterol
Acetyl CoA – C27
Synthesis – cytosolic compartmentEndoplasmic reticulum bound enzymes
All cellsLIVERAdrenal cortexTestisOvariesIntestinal epithelia
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Steps of cholesterol biosynthesis I
Biosynthesis of membrane lipids and steroids 1
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mevalonateCoAglutarylmethyl3hydroxy3
CoAglutarylmethyl3hydroxy3CoA-acetyl CoA lacetoacety
CoAlacetoacetyCoA-acetyl 2
reduktase-CoA-HMG
syntaseCoA HMG
thiolase
Koleszterin-bioszintézis
Ketontest-képzés
-OOC
CH3 OH
CoA
O
-OOC
CH3 OH OH
3-Hidroxi-3metil-glutaril-CoA mevalonát
2 NADPH+H+ 2 NADP+
CoASH
HMG-CoA reduktáz
Steps of cholesterol biosynthesis IIRate limiting step in cholesterol biosynthesis
Biosynthesis of membrane lipids and steroids 1
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Steps of cholesterol biosynthesis IIIMevalonic acid + ATP 5-pyrophospho-mevalonate
5-pyrophospho-mevalonate decarboxylation + active isoprenoid unit
Biosynthesis of membrane lipids and steroids 1
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Prenylated proteins, ubiquinon, heme,
Steps of cholesterol biosynthesis IVDimethylallyl-PP + isopentenyl-PP = Geranyl-PP (5 + 5) = 10
Geranyl –PP + isopentenyl-PP = farnesyl-PP (10 + 5) = 15
Farnesyl-PP + Farnesyl-PP = Squalene (15 + 15 )= 30
NADPH + H+ -PPi
Squalene -syntase – Endoplasmic reticulum
Biosynthesis of membrane lipids and steroids 1
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5
5
10
15
5
30
15
Steps of cholesterol biosynthesis VCyclizationMonooxygenaseC2,3 epoxide
Transfer of Methylgroups14-13, 8 – 14
Sterol carrier protein 1 (SCP1)Squalene
Sterol carrier protein 2 (SCP2)Lanosterol
Biosynthesis of membrane lipids and steroids 1
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Steps of cholesterol biosynthesis V1 molecule of cholesterol
18 acetyl-CoA36 ATP16 NADPH
Biosynthesis of membrane lipids and steroids 1
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Regulation of cholesterol biosynthesis
• Regulation of HMG-CoA biosynthesis– HMG-CoA reductase mRNS
synthesis (transcription)– HMG-CoA reductase mRNS
translation– HMG-CoA reductase
degradation– covalent modification -
phosphorylation
Cholesterol - foodde novo synthesis
LiverIntestine
Rate of biosynthesis is influenced byIntracellular cholesterin synthesis
Comitted step: HMG-CoA reductase
Biosynthesis of membrane lipids and steroids 1
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REGULATION OF CHOLESTEROL BIOSYNTHESISRegulation of biosynthesis of HMG-CoA
HMG-CoA reductase mRNS synthesis (transcription) HMG-CoA reductase mRNS translationHMG-CoA reductase degradationcovalent modification - phosphorylation
Sterol regulatory element binding protein (SREBP)
SREBP cleavage activating protein (SCAP)
Biosynthesis of membrane lipids and steroids 1
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HMG-CoA reductase
CholesterolCholesterolCholesterol
INSIG-1
REGULATION OF CHOLESTEROL BIOSYNTHESISRegulation of biosynthesis of HMG-CoA
HMG-CoA reductase mRNS synthesis (transcription)HMG-CoA reductase mRNS translationHMG-CoA reductase degradationcovalent modification - phosphorylation
Sterol regulatory element binding protein (SREBP)
SREBP cleavage activating protein (SCAP)
Biosynthesis of membrane lipids and steroids 1
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X formed from mevalonateX formed from mevalonate
cholesterol of food origin cholesterol of food origin
REGULATION OF CHOLESTEROL BIOSYNTHESISRegulation of biosynthesis of HMG-CoA
HMG-CoA reductase mRNS synthesis (transcription)HMG-CoA reductase mRNS translationHMG-CoA reductase degradationcovalent modification - phosphorylation
Sterol regulatory element binding protein (SREBP)
SREBP cleavage activating protein (SCAP)
HMG-CoA reductaseCytoplasmatic domain – katalysisMembrane domain – sensor cholesterol ccEnzyme proteolytic cleavage, ubiquitine, proteasome
Biosynthesis of membrane lipids and steroids 1
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REGULATION OF CHOLESTEROL BIOSYNTHESISRegulation of biosynthesis of HMG-CoA
HMG-CoA reductase mRNS synthesis (transcription)HMG-CoA reductase mRNS translationHMG-CoA reductase degradationcovalent modification - phosphorylation
Sterol regulatory element binding protein (SREBP)
SREBP cleavage activating protein (SCAP)
Biosynthesis of membrane lipids and steroids 1
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LIPIDTRANSPORT
Biosynthesis of membrane lipids and steroids 1
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Hepatocyta - VLDL
Biosynthesis of membrane lipids and steroids 1
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Chylomicrons
Biosynthesis of membrane lipids and steroids 1
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VLDL
Biosynthesis of membrane lipids and steroids 1
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HDL
Biosynthesis of membrane lipids and steroids 1
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LDL
Biosynthesis of membrane lipids and steroids 1
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Biosynthesis of membrane lipids and steroids 1
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Bile acids
OH
OH OHH
OH
COOH
OH OHH
COOH
OHH
OH
COOH
Biosynthesis of membrane lipids and steroids 1
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OHH
COOHCholesterolCholesterol
Primary bile acidPrimary bile acid
Secondary bile acidsSecondary bile acids
Cholic acid
Chenodeoxycholic acidChenodeoxycholic acid
Deoxycholic acid
Litocholic acid
Tauro ~Glyco ~
Tauro ~Gliko ~
NH
CH2 CH2 SO3H
NH
CH2 COOH
Biosynthesis of bile acids
Biosynthesis of membrane lipids and steroids 1
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Enterohepatic circulation
Biosynthesis of membrane lipids and steroids 1
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Bile: bile acids, phosphatidyl-choline, cholesterol
Biosynthesis of membrane lipids and steroids 1
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cholesterol %phosphatidylcholine %
Bile acid %
5, 15, 80 %
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