Biosynthesis of membrane lipids and steroids 1
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Biosynthesis of membrane lipids and steroids 1. Léránt István. BIOSYNTHESIS OF MEMBRANE LIPIDS. Fatty acid 1. Fatty acid 1. Glycerol. Fatty acid 2. Glycerol. Fatty acid 2. Phosphatydic acid is a COMMON INTERMEDIER of biosynthesis of phospholipids Neutral fats. Fatty acid 3. P.

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Biosynthesis of membrane lipids and steroids 1

Biosynthesis of membrane lipids and steroids 1

Léránt István


Biosynthesis of membrane lipids

BIOSYNTHESIS OF MEMBRANE LIPIDS

  • Fattyacid 1

  • Fattyacid 1

  • Glycerol

  • Fattyacid 2

  • Glycerol

  • Fattyacid2

Phosphatydic acid is a

COMMON INTERMEDIER of biosynthesis of

phospholipids

Neutral fats

  • Fattyacid3

P

Alcohol

Glycerol-phosphate

acyltransferase

Neutralfats

Phospholipids

Biosynthesis of membrane lipids and steroids 1


Biosynthesis of membrane lipids and steroids 1

In most tissues

Glycerol / glycerol-kinase

LIver

Adiposetissue:

Glycolysis - DHAP

Biosynthesis of membrane lipids and steroids 1


Synthesis of membrane lipids and triglycerids

SYNTHESIS of MEMBRANE LIPIDS and TRIGLYCERIDS

Phosphatydic acid is a

COMMON INTERMEDIER of biosynthesis of

phospholipids

Neutral fats

ACYL-GLYCEROL-SYNTHETASE COMPLEX

ENDOPLASMIC RETICULUM

Phosphatase

Diacylglycerol acyltransferase

Biosynthesis of membrane lipids and steroids 1


Synthesis of membrane lipids

SYNTHESIS OF MEMBRANE LIPIDS

BIOSYNTHESIS OF PHOSPHOLIPIDS

ACTIVATION OF PHOSPHATIDIC ACID / ALCOHOL

Biosynthesis of membrane lipids and steroids 1


Synthesis of phosphatidylinositol 4 5 bisphosphate

SYNTHESIS OF PHOSPHATIDYLINOSITOL 4,5 BISPHOSPHATE

CDP-diacylglycerol

Phosphatidyl-inositol

Phosphatidyl-inositol

4,5 bisphosphate

Phospholipase C

Biosynthesis of membrane lipids and steroids 1


Cardiolipin component of the mitochodrial membranes

Cardiolipin - component of the mitochodrial membranes

Phosphatidyl - glycerol

Diophosphatidyl – glycerol; Cardiolipin

P-

P-

pH ~ / = 7,0 pK’ H3PO4 ~ / = 1 - 2

Mitochondria / Lues

Biosynthesis of membrane lipids and steroids 1


Cardiolipin component of the mitochodrial membranes1

Cardiolipin - component of the mitochodrial membranes

CTP

CDP

P-

P-

Biosynthesis of membrane lipids and steroids 1


Phosphatidyl choline

PHOSPHATIDYL-CHOLINE

CHOLINE:

Foodsources

Circulation

Presynapticcholinergicmembrane

Choline-transport - highaffinitySynthesis of phosphatidyl-cholinein hepatocytesfromphosphatidyl-ethanolamine

Cytoplasm

Endoplasmicreticulum

CTP:phosphocholine

cytidyliltranspherase

Choline-kinase

CDP-CHOLINE: 1,2-diglyceride

Phosphocholineltranspherase

Endoplasmicreticulum

Biosynthesis of membrane lipids and steroids 1


Phosphatidylethanolamine phosphatidyl choline liver

CHOLINE

PHOSPHATIDYLETHANOLAMINE&PHOSPHATIDYL-CHOLINELIVER

CHOLINE-P

CDP-CHOLINE

PHOSPHATIDYL-

CHOLINE

CO2

3 S-adenosyl-

homocysteine

3 SAM

PHOSPHATIDYL

SERINE

Biosynthesis of membrane lipids and steroids 1


Phosphatidylethanolamine phosphatidyl choline liver1

CHOLINE

PHOSPHATIDYLETHANOLAMINE&PHOSPHATIDYL-CHOLINELIVER

CHOLINE-P

RATE LIMITING STEP:

CTP:phosphocholine cytidylil-transferase

Cytoplasm – Endoplasmic reticulum

Translocation - activation

+ fatty acid – fatty -acyl-CoA / DAG

cAMP dependent protein kinase

Lipid transport – PCh dependent

Choline deficiency / VLDL / fatty liver

CDP-CHOLINE

PHOSPHATIDYL-

CHOLINE

CO2

3 S-adenosyl-

homocysteine

3 SAM

PHOSPHATIDYL

SERINE

Biosynthesis of membrane lipids and steroids 1


Sphingolipids

Sphingolipids

Sphingosine

Sphingosine

  • Fattyecid

  • Fattyacid

Ceramide

Glu / Gal

P

Choline

Sphingosine (4-sphingenene)

  • X

Sphingomyeline

P

Choline

Glu

Glucosyl-cerebroside

Sphingosine

  • Fattyacid

Glu

Gal

Lactosyl-cerebrozide

NeuNAc

  • X

GM2ganglioside

Glu

Gal

GalNAc

Biosynthesis of membrane lipids and steroids 1


Sphingomyelin

Sphingomyelin

Fattyacid

Phosphoricacid

Sphingosine

Ceramide

Choline

Biosynthesis of membrane lipids and steroids 1


Synthesis of sphigolipids

Synthesis of sphigolipids

Galactocerebrosides

Glucocerebrosides

Gangliosides

sphyngomyeline

Biosynthesis of membrane lipids and steroids 1


Biosynthesis of membrane lipids and steroids 1

Biosynthesis of membrane lipids and steroids 1


Glucosyl ceramide glucocerebroside

Glucosyl-ceramide / Glucocerebroside

Monohexoside

Glu

Ceramide

Dihexoside

Gal

Glu

Ceramide

Trihexoside

Gal

Gal

Glu

Ceramide

Biosynthesis of membrane lipids and steroids 1


Galactosyl ceramide galactocerebroside

Galactosyl – ceramide / Galactocerebroside

Monohexoside

Gal

Ceramid

Dihexozid

Gal

Gal

Ceramid

Biosynthesis of membrane lipids and steroids 1


Abo blood group system

ABO blood group system

Glu

Gal

GalNAc

Gal

„O” (H) antigen

Fuc

Glu

Gal

GalNAc

Gal

GalNAc

„A” antigen

Fuc

Glu

Gal

GalNAc

Gal

Gal

„B” antigen

Fuc

Biosynthesis of membrane lipids and steroids 1


Gangliosides

Gangliosides

Glu

Gal

Ceramide

GM3

NANA

GM2

GalNAc

Gal

Glu

Ceramide

NANA

GM1

GalNAc

Gal

Glu

Ceramide

Cholera toxin

Gal

NANA

Biosynthesis of membrane lipids and steroids 1


Inborn errors of phospholipid sphingolipid metabolism

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


    Sphingolipidoses

    Sphingolipidoses

    sphingomyelinase

    Niemann-Pick

    Ceramid

    P-Kol

    • Accumulation of sphingomyelin

    Biosynthesis of membrane lipids and steroids 1


    Gaucher s disease

    Gaucher’s - disease

    • Accumulation of glucocerebrosides in reticuloendothelial cells of spleen, liver, and bone marrow

    • the most common of lysosomal storage disease

    • Mental retardation

    Glu

    b-glukozidáz

    Gaucher

    Ceramid

    Biosynthesis of membrane lipids and steroids 1


    Krabbe disease

    Krabbe disease

    • Accumulation of Galactosyl ceramide

    Gal

    b-galaktosidase

    Krabbe

    Ceramid

    Biosynthesis of membrane lipids and steroids 1


    Tay sachs disease

    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


    Tay sachs disease1

    Tay – Sachs Disease

    Glu

    Gal

    GalNAc

    Tay - Sachs

    Ceramid

    NANA

    hexosaminidase

    Biosynthesis of membrane lipids and steroids 1


    Sphingolipidoses1

    Sphingolipidoses

    Glu

    Gal

    Gal

    Fabry

    Ceramide

    a-galactosidase

    Biosynthesis of membrane lipids and steroids 1


    Cholesterol

    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 Goldstein

    Nobel Lectures (1985)

    Biosynthesis of membrane lipids and steroids 1


    Cholesterol1

    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 Goldstein

    Nobel Lectures (1985)

    Biosynthesis of membrane lipids and steroids 1


    Cholesterol2

    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 Goldstein

    Nobel Lectures (1985)

    Biosynthesis of membrane lipids and steroids 1


    Cholesterol3

    CHOLESTEROL

    • SYNTHESIS OF

    • Active isoprenoid-units – isopentenyl-pirophosphate

    • Acetyl-CoA à3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA)

      • HMG-CoA àmevalonate

      • Mevalonate àisopentenyl-PP

    • 6 isopentenyl-pyrophosphate àsqualen

    • Cyclisation of squalen àcholesterol

    Acetyl CoA – C27

    Synthesis – cytosolic compartment

    Endoplasmic reticulum bound enzymes

    All cells

    LIVER

    Adrenal cortex

    Testis

    Ovaries

    Intestinal epithelia

    Biosynthesis of membrane lipids and steroids 1


    Steps of cholesterol biosynthesis i

    Steps of cholesterol biosynthesis I

    Koleszterin-bioszintézis

    Ketontest-képzés

    Biosynthesis of membrane lipids and steroids 1


    Steps of cholesterol biosynthesis ii

    Steps of cholesterol biosynthesis II

    Rate limiting step in cholesterol biosynthesis

    Biosynthesis of membrane lipids and steroids 1


    Steps of cholesterol biosynthesis ii i

    Steps of cholesterol biosynthesis III

    Mevalonicacid + ATP à

    5-pyrophospho-mevalonate

    5-pyrophospho-mevalonate àdecarboxylation + activeisoprenoid unit

    Prenylatedproteins, ubiquinon, heme,

    Biosynthesis of membrane lipids and steroids 1


    Steps of cholesterol biosynthesis iv

    Steps of cholesterol biosynthesis IV

    5

    5

    Dimethylallyl-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

    10

    5

    15

    15

    30

    Biosynthesis of membrane lipids and steroids 1


    Steps of cholesterol biosynthesis v

    Steps of cholesterol biosynthesis V

    Cyclization

    Monooxygenase

    C2,3 epoxide

    Transfer of Methylgroups

    14-13, 8 – 14

    Sterol carrier protein 1 (SCP1)

    Squalene

    Sterol carrier protein 2 (SCP2)

    Lanosterol

    Biosynthesis of membrane lipids and steroids 1


    Steps of cholesterol biosynthesis v1

    Steps of cholesterol biosynthesis V

    1 molecule of cholesterol

    18 acetyl-CoA

    36 ATP

    16 NADPH

    Biosynthesis of membrane lipids and steroids 1


    Regulation of cholesterol biosynthesis

    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 - food

    de novo synthesis

    Liver

    Intestine

    Rate of biosynthesis is influenced by

    Intracellular cholesterin synthesis

    Comitted step: HMG-CoA reductase

    Biosynthesis of membrane lipids and steroids 1


    Regulation of cholesterol biosynthesis1

    Cholesterolá

    Cholesterolâ

    REGULATION OF CHOLESTEROL BIOSYNTHESIS

    Regulation of biosynthesisofHMG-CoA

    HMG-CoA reductase mRNSsynthesis (transcription)

    HMG-CoA reductase mRNStranslation

    HMG-CoA reductase degradation

    covalentmodification - phosphorylation

    Sterolregulatoryelementbinding protein (SREBP)

    SREBP cleavageactivating protein (SCAP)

    INSIG-1

    HMG-CoA reductase

    Biosynthesis of membrane lipids and steroids 1


    Regulation of cholesterol biosynthesis2

    REGULATION OF CHOLESTEROL BIOSYNTHESIS

    Regulation of biosynthesisofHMG-CoA

    HMG-CoA reductase mRNSsynthesis (transcription)

    HMG-CoAreductase mRNStranslation

    HMG-CoA reductase degradation

    covalentmodification - phosphorylation

    Sterolregulatoryelementbinding protein (SREBP)

    SREBP cleavageactivating protein (SCAP)

    X formedfrommevalonate

    cholesterol of foodorigin

    Biosynthesis of membrane lipids and steroids 1


    Regulation of cholesterol biosynthesis3

    REGULATION OF CHOLESTEROL BIOSYNTHESIS

    Regulation of biosynthesisofHMG-CoA

    HMG-CoA reductase mRNSsynthesis (transcription)

    HMG-CoA reductase mRNStranslation

    HMG-CoA reductase degradation

    covalentmodification - phosphorylation

    Sterolregulatoryelementbinding protein (SREBP)

    SREBP cleavageactivating protein (SCAP)

    HMG-CoA reductase

    Cytoplasmatic domain – katalysis

    Membrane domain – sensor cholesterol cc

    Enzyme proteolytic cleavage, ubiquitine, proteasome

    Biosynthesis of membrane lipids and steroids 1


    Regulation of cholesterol biosynthesis4

    REGULATION OF CHOLESTEROL BIOSYNTHESIS

    Regulation of biosynthesisofHMG-CoA

    HMG-CoA reductase mRNSsynthesis (transcription)

    HMG-CoA reductase mRNStranslation

    HMG-CoA reductase degradation

    covalentmodification - phosphorylation

    Sterolregulatoryelementbinding protein (SREBP)

    SREBP cleavageactivating protein (SCAP)

    Biosynthesis of membrane lipids and steroids 1


    Lipidtransport

    Hepatocyta - VLDL

    LIPIDTRANSPORT

    Biosynthesis of membrane lipids and steroids 1


    Biosynthesis of membrane lipids and steroids 1

    Biosynthesis of membrane lipids and steroids 1


    Chylomicrons

    Chylomicrons

    Biosynthesis of membrane lipids and steroids 1


    Biosynthesis of membrane lipids and steroids 1

    VLDL

    Biosynthesis of membrane lipids and steroids 1


    Biosynthesis of membrane lipids and steroids 1

    HDL

    Biosynthesis of membrane lipids and steroids 1


    Biosynthesis of membrane lipids and steroids 1

    LDL

    Biosynthesis of membrane lipids and steroids 1


    Biosynthesis of membrane lipids and steroids 1

    Biosynthesis of membrane lipids and steroids 1


    Biosynthesis of membrane lipids and steroids 1

    Biosynthesis of membrane lipids and steroids 1


    Biosynthesis of membrane lipids and steroids 1

    Biosynthesis of membrane lipids and steroids 1


    Bile acids

    Bile acids

    Tauro ~

    Gliko ~

    Tauro ~

    Glyco ~

    Cholesterol

    Chenodeoxycholicacid

    Litocholicacid

    Cholicacid

    Primarybileacid

    Deoxycholicacid

    Secondarybileacids

    Biosynthesis of membrane lipids and steroids 1


    Biosynthesis of bile acids

    Biosynthesis of bile acids

    Biosynthesis of membrane lipids and steroids 1


    Enterohepatic circulation

    Enterohepatic circulation

    Biosynthesis of membrane lipids and steroids 1


    Bile bile acids phosphatidyl choline cholesterol

    Bile: bileacids, phosphatidyl-choline, cholesterol

    phosphatidylcholine %

    cholesterol %

    5, 15, 80 %

    Bileacid %

    Biosynthesis of membrane lipids and steroids 1


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