Chapter 21 Chapter 21

Lipid BiosynthesisLipid Biosynthesis1. Fatty acids;

2. Eicosanoids;

3. Triacylglycerols;

4. Membrane phospholipids;

5. Cholesterol, steroids, and isoprenoids;

1.1. Fatty acid synthesis takes a different Fatty acid synthesis takes a different pathway from its degradationpathway from its degradation

Occurs in the cytosol (chloroplasts in plants).Acetyl-CoA provides the first two carbons, which is elongate

d by sequential addition of two-carbon units donated from malonyl-CoA.

Intermediates are attached to the -SH groups of an acyl carrier protein (ACP).

NADPH is the reductant.The enzymes are associated as a multi-enzyme complex or e

ven being in one polypeptide chain in higher organisms (fatty acid synthase).

Elongation by the fatty acid synthase complex stops upon formation of palmitate (C16), further elongation and desaturation are carried out by other enzyme systems.

2.2. Malonyl-CoA is formed from acetyl-CoMalonyl-CoA is formed from acetyl-Co

A and bicarbonateA and bicarbonate Salih Wakil discovered that HCO3

- is required for fatty acid synthesis.

Acetyl-CoA carboxylase (being trimeric in bacteria, monomeric in animals and both in plants) catalyzes this carboxylation reaction.

The enzyme has three functional parts: a biotin carrier protein; an ATP-dependent biotin carboxylase; and a transcarboxylase.

The enzyme exemplifies a ping-pong reaction mechanism.

This irreversible reaction commits acetyl-CoA to fatty acid synthesis.

biotin carboxylase

Trans-carboxylase

Acetyl-CoA carboxylasecatalyzes the two-step carboxylation reaction of acetyl-CoA in two active sites.

3. The acetyl and malony groups are first 3. The acetyl and malony groups are first transferred to two –SH groups of the fatttransferred to two –SH groups of the fatt

y acid synthase complexy acid synthase complexThe acetyl group of acetyl-CoA is first transferred to

the –SH group of a Cys residue on the -ketoacyl-ACP synthase (KS) in a reaction catalyzed by acetyl-CoA-ACP transacetylase (AT).

The malonyl group is transferred from malonyl-CoA to the –SH group of the 4`-phosphopantetheine covalently attached to a Ser residue of the acyl carrier protein (ACP).

The acyl carrier protein (ACP) is very similar to The acyl carrier protein (ACP) is very similar to CoA (thus can be regarded as “macro CoA”)CoA (thus can be regarded as “macro CoA”)

4. Fatty acids are synthesized by a repea4. Fatty acids are synthesized by a repeating four-step reaction sequenceting four-step reaction sequence

In the condensation reaction (step 1), catalyzed by -ketoacyl-ACP synthase, the methylene group of malonyl-CoA (linked to ACP) undergoes a nucleophilic attack on the carbonyl carbon of the acetyl group linked to KS, forming the -ketobutyryl-ACP with simultaneous elimination of CO2.

the -ketobutyryl-ACP is then reduced to D--hydroxybutyryl-ACP (step 2), using NADPH and the -ketobutyryl-ACP reductase (KR).

A water molecule is then removed from the -hydroxybutyryl-ACP to produce trans-2-butenoyl-ACP in a reaction catalyzed by -hydroxybutyryl-ACP dehydratase (step 3).

A further reduction (step 4), also using NADPH, of the carbon-carbon double in trans-2-butenoyl-ACP, catalyzed by enoyl-ACP reductase produces a saturated acyl on ACP (butyryl-ACP).

The butyryl group is then transferred to the Cys –SH group of -ketoacyl-ACP synthase for another round of four reactions, which will extend the chain by two more carbons.

Seven rounds of the four-step lengthening reactions produces palmitoyl-ACP, which will be hydrolyzed to release a free palmitate.

The flexible 4`-phosphopantetheine group covalently attached to ACP is believed to act as a switch arm to move the intermediates from one active site to the next on the enzyme complex (i.e., the substrates are channeled).

A total of 7 ATP and 14 NADPH will be consumed for making one palmitate molecule.

5. The seven activities of fatty acid synth5. The seven activities of fatty acid synthesis from different organisms have differesis from different organisms have differ

ent level of integrationent level of integrationEach activity resides in a separate polypeptide c

hain in bacteria and higher plants.The seven activities reside in two separate poly

peptide chains, with the synthase present as dodecamers (6 6).

The seven activities reside in one large polypeptide chain in vertebrates, with the synthase present as dimers.

The seven activitiesThe seven activities of fatty acid synthaseof fatty acid synthaseare integrated toare integrated todifferent levels indifferent levels indifferent organisms.different organisms.

6. Fatty acid synthesis occurs in cellular 6. Fatty acid synthesis occurs in cellular compartments having a high NADPH/NAcompartments having a high NADPH/NA

DPDP++ ratio ratioNAD and NADP have selected for functioning as el

ectron carriers in oxidative catablism and reductive anabolism respectively.

In the hepatocytes and adipocytes, NADPH is mainly produced in the cytosol via the pentose phosphate pathway and by the malic enzyme.

In photosynthetic plants, fatty acid synthesis occur in the chloroplast stroma, using NADPH made from photophosphorylation.

Malic Malic enzymeenzyme

Pentose phosphatePentose phosphatepathwaypathway

NADPH in the cytosol of animal cellsNADPH in the cytosol of animal cellsis largely produced by the oxidativeis largely produced by the oxidativedecarboxylation of malate and thedecarboxylation of malate and thepentose phosphate pathwaypentose phosphate pathway

7. The acetyl groups of the mitochondrio7. The acetyl groups of the mitochondrion are transported into the cytosol in the fn are transported into the cytosol in the f

orm of citrateorm of citrateThe acetyl-CoA molecules are made from glucose

and amino acids in mitochondria.The are shuttled into the cytosol in the form of citra

te via the citrate transporter of the inner membrane.Acetyl-CoA is regenerated by the action of ATP-de

pendent citrate lyase in the cytosol.Oxaloacetate is shuttled back into the mitochondria

as malate or pyruvate.

8. The rate of fatty acid biosynthesis is 8. The rate of fatty acid biosynthesis is controlled by acetyl-CoA carboxylasecontrolled by acetyl-CoA carboxylase

Excess fuel is generally converted to fatty acids/triacylglycerol for longer term storage.

Acetyl-CoA carboxylase, catalyzing the committing and rate-limiting step of fatty acid synthesis, is allosterically inhibited by palmitoyl-CoA and activated by citrate.

Glucagon and epinephrine triggers the phosphorylation and disassociation of the polymeric enzyme subunits, which inactivates the enzyme.

Citrate partially activate the phosphorylated acetyl-CoA carboxylase (similar to how AMP partially active the dephosphorylated glycogen phosphorylase).

In plants, acetyl-CoA carboxylase is activated by a increase of Mg 2+ concentration and decrease of H+ concentration that accompany illumination.

(Malonyl-CoA inhibits carnitine acyltransferase I)

Dephosphorylatedacetyl-CoA Carboxylase (active)

Acetyl-CoA carboxylaseis regulated by allostericeffectors and reversiblephosphorylation

Citrate partially activate the phosphorylatCitrate partially activate the phosphorylated acetyl-CoA carboxylaseed acetyl-CoA carboxylase

9. Palmitate can be further elongated and 9. Palmitate can be further elongated and desaturated in smooth ERdesaturated in smooth ER

Palmitoyl-CoA can be further elongated by the fatty acid elongation system present mainly in the smooth endoplasmic reticulum, with two-carbon units also donated by malonyl-CoA.

Palmitoyl-CoA and Stearoyl-CoA can be desaturated between C-9 and C-10 to produce palmitoleate, 16:1(9), and oleate, 18:1(9) respectively.

The double bonds are introduced by the catalysis of fatty acyl-CoA desaturase (a mixed-function oxidase), where both the fatty acyl group and NADPH are oxidized by O2.

The electrons of NADPH are transferred to O2 via Cyt b5 reductase and cytochrome b5.

Further desaturation of oleate occur on phosphatidylcholine and is catalyzed by another desaturase, which is present only in plant cells.

Linoleate and linolenate, needed to make other polyunsaturated fatty acids like arachidonate are essential fatty acids for mammals.

Palmitate is the Palmitate is the Precursor for the Precursor for the biosynthesis ofbiosynthesis ofother fatty acidsother fatty acids

Fatty acyl-CoA is desaturated (oxidized) Fatty acyl-CoA is desaturated (oxidized) by Oby O22 and NADPH. and NADPH.

Oleate can be desaturated on Phosphatidylcholine(often attaching to C-2)to form linoleate and linolenate

10. Eicosanoids are derived from arachi10. Eicosanoids are derived from arachidonate, 20:4 (donate, 20:4 (5,8,11,145,8,11,14))

The arachidonate (花生四烯酸 ) is first cleaved off from membrane phospholipids by phospolipase A2, in response to hormonal or other stimuli.

Arachidonate is then converted to PGH2 by the catalysis of the bifunctional cyclooxygenase (COX): the cyclooxygenase activity converts arachidonate to PGG2; the peroxidase activity then converts PGG2 to PGH2.

PGH2 is the immediate precursor of other prostaglandins and thromboxanes.

Aspirin (acetylsalicylate) irreversibly inhibits the cyclooxygenase by acetylating an active site Ser, thus blocking the synthesis of prostglandins and thromboxanes; Ibuprofen also inhibit the same enzyme.

Arachidonate can also be modified by adding hydroperoxy groups at various positions to form various hydroperoxyeicosatetraenoates (HPETEs) in reactions catalyzed by various lipooxygenases with the incorporation of O2.

The HPETEs will be further converted to leukotrienes (白细胞三烯 ).

Prostaglandins andthromboxanes are synthesized from arachidonate

Cyclooxygenaseactivity of COX

Peroxidaseactivity of COX

The dimeric bifunctional cyclooxygenase(COX-1)

Heme for the peroxidaseactive site

Tyr385, a keyresidue for thecyclooxygenaseactivity

flurbiprofen

Ser530

11. Newly synthesized fatty acids have m11. Newly synthesized fatty acids have mainly two alternative fates in cellsainly two alternative fates in cells

Fate I: be incorporated into triacylglycerols as a form to store metabolic energy in long terms.

Fate II: be incorporated into membrane phospholipids (during rapid growth).

12. Phosphatidic acid is the common pre12. Phosphatidic acid is the common precursor for the syntheses of both triacylglcursor for the syntheses of both triacylgl

ycerols and glycerophospholipidsycerols and glycerophospholipids

Phosphatidic acid (or diacylglycerol 3-phosphate) is made by transferring two acyl groups from two acyl-CoAs to L-glycerol 3-phosphate, which is derived from either glycerol or dihydroxyacetone phosphate.

A phosphatidic acid is converted to a triacylglycerol via a dephosphorylation reaction (catalyzed by phosphatidic acid phosphatase) and a acyl transferring reaction.

Phosphatidic Phosphatidic acid is derivedacid is derivedfrom L-glycerol 3-from L-glycerol 3-phosphate and twophosphate and twoacyl-CoAs.acyl-CoAs.

Often unsaturatedOften unsaturatedOften saturatedOften saturated

Phosphatidic acidPhosphatidic acidphosphatasephosphatase

Phosphatidic acidPhosphatidic acidis the commonis the commonprecursor for bothprecursor for bothtriacylglycerols and triacylglycerols and glycerophospholipidsglycerophospholipids

13. Insulin stimulates conversion of dieta13. Insulin stimulates conversion of dietary carbohydrates/proteins into fatry carbohydrates/proteins into fat

Diabetes patients due to lack of insulin would neither be able to use glucose properly, nor to synthesize fatty acids from carbohydrates and amino acids.

They show increased rates of fatty acid oxidation and ketone body formation, thus losing weight.

14. Two strategies are taken for converti14. Two strategies are taken for converting phosphatidic acid to glycerophospholng phosphatidic acid to glycerophosphol

ipidipidEugene Kennedy revealed in 1960s that either the –

OH group of the diacylglycerol (strategy 1) or that of the polar head (strategy II) is first activated by attaching to cytidine nucleotide.

The CMP moiety is displaced by the other –OH group in a nucleophilic attack reaction to synthesize a glycerophospholipid.

Both strategies are used in eukaryotic cells, but only strategy I is use in bacterial cells.

Bacteria mainly usethis strategy

Eukaryotic cellsuse both strategies(occurring on sER andinner membrane of mitochondria)

phosphatase decarboxylase

Phospholipid synthesisin E. coli employsCDP-diacylglcerol

15. Acidic (anionic) phospholipids in euk15. Acidic (anionic) phospholipids in eukaryotic cells are synthesized using CDP-aryotic cells are synthesized using CDP-

diacylglyceroldiacylglycerol

These include phosphatidylglycerol, cardiolipin, phosphatidylinositol, phosphatidylserine.

eukaryotic cardiolipin is synthesized from one phosphatidylglycerol and one CDP-diacylglycerol (from two phosphatidylglycerols in bacteria).

44

55

16. Phosphatidyl choline (PC) and phosp16. Phosphatidyl choline (PC) and phosphatidyl ethanolamine (PE) are often madhatidyl ethanolamine (PE) are often made from the salvage (reuse) pathway in mae from the salvage (reuse) pathway in ma

mmalsmmalsDiet choline and ethanolamine are first conver

ted to CDP-choline and CDP-ethanolamine after an initial phosphorylation step.

The CMP moiety is then replaced by a diacylglycerol, forming PC and PE.

Phosphatidylserine (PS) is often made from PE by a head exchange reaction (reversible).

PC can be made from PE by three methylation reactions using S-adenosylmethionine (adoMet) in the liver cells.

PS can also be converted to PE by a decarboxylation reaction.

(ethanolamine)(ethanolamine)

(Phosphoethanolamine)(Phosphoethanolamine)

(CDP-ethanolamine)(CDP-ethanolamine)

(Phosphatidylthanolamine)(Phosphatidylthanolamine)

PC and PE are PC and PE are made from themade from thesalvage pathwaysalvage pathway in mammalsin mammals

The synthesis of PE,The synthesis of PE,PC, PS in eukaryoticPC, PS in eukaryoticcells.cells.

17. The synthesis of ether lipids involves 17. The synthesis of ether lipids involves a displacement of fatty acyl by fatty alcoa displacement of fatty acyl by fatty alco

hol step and a desaturation stephol step and a desaturation step

Both plasmalogen (缩醛磷脂 ) and platelet-activating factor are made using this pathway.

The acyl group on 1-acyldihydroxyacetone 3-phosphate is replaced by a long chain alcohol group to form the ether linkage.

The double bond in plasmalogen is introduced at the end by the catalysis of a mixed-funciton oxidase.

Synthesis of Synthesis of the ether lipids the ether lipids ((醚脂类醚脂类））

1-alkylglycerol 3-phosphate1-alkylglycerol 3-phosphate

18. The sphingosine backbone of spingol18. The sphingosine backbone of spingolipids is derived from palmitoyl-CoA and ipids is derived from palmitoyl-CoA and

SerSerPalmitoyl-CoA condenses with serine (PLP is neede

d for decarboxylate serine) to form -ketosphinganine, which is then reduced to sphinganine (二氢鞘氨醇 ).

Sphinganine is then acylated and desaturated to form ceramide (containing sphingosine).

Addition of sugar(s) or phosphocholine heads leads to the synthesis of cerebroside, gangliosides, or sphingomyelin.

The ways for the membrane lipids (glycerolphospholipids and spingolipids) synthesized at smooth endoplasmic reticulum or inner membrane of Mitochondria to be transported to specific cellular locations are not well understood yet.

PLP

Spingolipid synthesis beginswith the condensation betweenpalmitoyl-CoA and Ser.

(not CDP-choline!)(not CDP-choline!)

A glycolipid, not aA glycolipid, not aphospholipidphospholipid

19. Radioisotope tracer experiments reve19. Radioisotope tracer experiments revealed that all the 27 carbons of cholesteroaled that all the 27 carbons of cholestero

l is derived from acetyl-CoAl is derived from acetyl-CoAThe origin of the carbon atoms of cholesterol was deduced

from tracer experiments where either with the methyl carbon or the carboxyl carbon in acetate is labeled with 14C (1940s).

The pattern of labeling provided the blueprint for revealing the detail enzymatic steps for cholesterol biosynthesis occurring in mammals.

The 30-carbon squalene (of six isoprene units) and later on mevalonate were found to be intermediates of cholesterol biosynthesis.

The biosynthetic pathway of cholesterol, being the most complex known, was elucidated mainly by Konrad Bloch and Feodor Lynen in the 1950s.

The carbon origins of cholesterol as revealed byradioisotope labeling studies.

20. The cholesterol biosynthesis pathwa20. The cholesterol biosynthesis pathway can be divided into four stagesy can be divided into four stages

Stage I: three acetyl-CoA molecules condense to form the 6-carbon mevalonate (甲羟戊酸 ).

Stage II: mevalonate is converted to activated 5-carbon isoprene (异戊二烯 ) units.

Stage III: Six isoprene units condense to form the linear 30-carbon squalene(鲨烯 ).

Stage IV: The linear squalene is cyclized to form a four-ring structure, which is eventually converted to the 27-carbon cholesterol through a series of complicated reactions.

(6C)

(5C)

(30C)

(27C)

(2C) Reactions assemblingcholesterol from 18 molecules of acetyl-CoAcan be divided into four stages.

21. Mevalonate commits the acetyl group21. Mevalonate commits the acetyl group

s for cholesterol synthesiss for cholesterol synthesis One molecule of -hydroxy--methylglutaryl-CoA (H

MG-CoA) is formed from three acetyl-CoA molecules in the cytosol via the same reactions as occurring in mitochondria for ketone body formation.

HMG-CoA reductase (an integrated membrane protein in the smooth ER) catalyzes the irreversible reduction of HMG-CoA (using two molecules of NADPH) to form mevalonate: committing the acetyl groups for cholesterol synthesis (thus being a major regulation step).

The irreversibleThe irreversiblecommitting stepcommitting stepfor cholesterolfor cholesterolbiosynthesisbiosynthesis

HMG-CoAHMG-CoAReductaseReductaseIn cytosolIn cytosol

One mevalonate isOne mevalonate issynthesized fromsynthesized fromthree acetyl-CoAthree acetyl-CoAmolecules.molecules.

Acetyl-CoA + acetoacetateAcetyl-CoA + acetoacetate

HMG-CoA lyaseHMG-CoA lyase in mitochondriain mitochondria

22. Two activated isoprenes are formed f22. Two activated isoprenes are formed from mavelonate after going through threrom mavelonate after going through thre

e phosphorylation stepse phosphorylation stepsThree phosphate groups are transferred from three A

TP molecules to mevalonate to form 3-phospho-5-pyrophosphomevalonate.

The leaving of both the carboxyl and the 3-phosphate groups leads to the formation of 3-isopentenyl pyrophosphate.

3-Isopentenyl pyrophosphate is isomerized to form the second activated isoprene: dimethylallyl pyrophosphate.

Two activatedTwo activatedisoprenes are isoprenes are formed fromformed frommavelonate.mavelonate.

23. The 30-carbon linear squalene is for23. The 30-carbon linear squalene is formed from the condensation of six activatmed from the condensation of six activat

ed isoprene unitsed isoprene unitsA dimethylallylpyrophosphate is joined to an isopen

tenylpyrophosphate (head-to-tail) to form the 10-carbon geranyl pyrophosphate.

A geranyl pyrophosphate is joined to another 3-isopentenyl pyrophosphate (head-to-tail) to form the 15-carbon farnesyl pyrophosphate(法呢基焦磷酸 ).

Two farnesyl pyrophosphate join (head-to-head) to form the 30-carbon squalene.

Farnesyl pyrophosphateis formed fromthree activatedisoprene units

15-carbon

Squalene is formedfrom the condensationof two farnesylpyrophosphates

24. The rings of cholesterol are formed vi24. The rings of cholesterol are formed via a concerted reaction across four doubla a concerted reaction across four double bonds of the linear squalene epoxide ine bonds of the linear squalene epoxide in

termediatetermediate Squalene 2,3-epoxide, is first formed in a reaction cat

alyzed by squalene monooxygenase using O2 and NADPH.

Concerted movement of electrons through four double bonds and the migration of two methyl groups generates lanosterol (羊毛固醇 ).

Lanosterol is converted to cholesterol via about 20 enzymatic reactions including many double bond reduction and demethylations.

Squalenemonooxygenase

cyclase

~ 20reactions

Oxygenation inducedring closing convertsthe linear squalene to lanosterol of fourrings, which is converted tocholesterolafter going throughanother 20 or soreactions!

25. Cholesterols made in vertebrate liver25. Cholesterols made in vertebrate livers can be converted to bile acids and chols can be converted to bile acids and chol

esterol esters before exportingesterol esters before exporting

Cholesterol can be converted to bile acids and bile salts, which will be secreted to the intestine for emulsifying lipids.

Cholesterol can also be converted to the more hydrophobic cholesterol esters, which will be stored in the liver or transported to other tissues after being incorporated into lipoprotein particles.

Cholesterol can be convertedCholesterol can be converted to bile acids (salts) to bile acids (salts) ：： glycocholate and taurocholateglycocholate and taurocholate

（甘胆酸盐）（甘胆酸盐）

牛黄胆酸盐牛黄胆酸盐

Acyl-CoA-CholesterylAcyl-CoA-Cholesterylacyl transferaseacyl transferase(ACAT) catalyzes the (ACAT) catalyzes the addition of an acyl addition of an acyl group to the hydroxyl group to the hydroxyl group of cholesterolgroup of cholesterol

26. Lipids (including cholesterols) are tr26. Lipids (including cholesterols) are transported in the vertebrate plasmia as ansported in the vertebrate plasmia as

various lipoprotein particlesvarious lipoprotein particlesThe different lipoprotein particles, having different

combinations of lipids and apolipoproteins, can be separated by untracentrifugation due to different densities and sizes.

The human plasma lipoproteins include chylomicrons (which transports lipids from intestine to various tissues), VLDL (very low density lipoproteins), LDL(Low density lipoproteins), HDL (high density lipoproteins).

At least nine apolipoproteins (named as apo A, B, C, D, E) have been revealed in human, which act as signals to target the lipoprotein particles to various tissues or activating enzymes that will act on the lipoproteins.

Endogenous lipids made in liver are transported to other tissues as VLDL particles (~ 87% lipids and 12% proteins).

The apoC-II protein in VLDL activates the lipoprotein lipase in muscle and adipocyte tissues, thus releasing free fatty acids there.

Some VLDL remnants is then converted to LDL (with 23% proteins and 75% lipids) and with the others being absorbed by the liver cells via receptor-mediated endocytosis.

LDL delivers cholesterols to extrahepatic tissues, where its apoB-100 protein (4636 residues) is recognized by specific LDL receptors and LDL is endocytosed.

HDL, with its precursors formed in the liver or intestine cells, collects the cholesterols in the plasma and deliver them to the liver cells.

(A negative correlation between blood HDL level and arterial diseases has been observed.)

Lipids are transportedLipids are transportedas various lipoprotein as various lipoprotein particles in vertebrateparticles in vertebrateplasmaplasma

LDL is uptaken by cellsLDL is uptaken by cellsvia the LDL receptors,via the LDL receptors,

LDL receptors are recycled to the cell surfaces

27. The de novo synthesis of cholestero27. The de novo synthesis of cholesterol is regulated to complement dietary intl is regulated to complement dietary int

akeakeHMG-CoA reductase, catalyzing the rate-limiting step o

f the de novo cholesterol synthesis, has an activity variable over 100 fold!

An yet characterized sterol promotes proteolytic degradation of HMG-CoA reductase and inhibits the transcription of the genes of HMG-CoA reductase and LDL receptor.

Hormones (insulin and glucagon) regulate the activity of the HMG-CoA reductase via reversible phosphorylation.

Genetic defect of the LDL receptor was found to cause the familial hypercholesterolemia and atherosclerosis: the LDL cholesterols can not enter the cells, while de novo synthesis continues despite the high cholesterol level in the blood.

Mevalonate analogs (e.g., compactin and lovastatin) can be used to treat patients with familial hypercholesterolemia.

The de novo synthesis of The de novo synthesis of cholesterol is regulatedcholesterol is regulatedto complement the to complement the dietary uptakedietary uptake

(For storage)(For storage)

The mevalonate analogsThe mevalonate analogsare used to treatare used to treathypercholesterolemiahypercholesterolemiapatients.patients.

28. Pregnenolone, the common precurso28. Pregnenolone, the common precursor of all steroid hormones, is derived from r of all steroid hormones, is derived from

cholesterolcholesterolThe tail chain of cholesterol is first hydroxylated at C20 a

nd C22, and then cleaved between these two carbons to remove a 6-carbon unit, forming pregnenolone(孕烯醇酮 ).

The hydroxylation is catalyzed by cytochrome P450 monooxygenases (a mitochondrial enzyme) that utilize NADPH and O2.

Cytochrome P450 is a large family of enzymes with different substrate specificity, hydroxylates many hydrocarbon chains.

cytochrome P450monooxygenases

Desmolase碳链裂解酶

Prognenolone, the common precursorof steroid hormones,is synthesized from cholesterol

29. All steroid hormones are derived fro29. All steroid hormones are derived from cholesterolm cholesterol

Progesterone (孕酮 ) is synthesized from pregnenolone by oxidizing the 3-OH group and the isomerization of the double bond (from 5 to 4 position).

Cortisol (a major glucocorticoid) is synthesized from progesterone by hydroxylation at C-17, C-21, and C-11.

Aldosterone (a mineralocorticoid) is synthesized from progesterone by hydroxylation at C-21, C-11, and oxidation of C-18 to an aldehyde.

Testosterone (an androgen, or male hormone) is synthesized from progesterone by the removal of 2-carbon unit and hydroxylation at C-17.

Estradiol ( an estrogen, or female hormone) is synthesized from testosterone by the removal of C-19 and formation of the aromatic A ring.

ProgesteroneProgesterone is synthesized from pregnenolone is synthesized from pregnenolone by oxidizing the 3-OH group and the isomerizatioby oxidizing the 3-OH group and the isomerizatio

n of the double bond from n of the double bond from 55 to to 4 4 positionposition

Cortisol and aldosterone Cortisol and aldosterone are synthesized from are synthesized from progesterone by several progesterone by several oxygenation reactionsoxygenation reactions (forming hydroxyl and (forming hydroxyl and aldehyde groups)aldehyde groups)

TestosteroneTestosterone is synthesized from is synthesized from progesterone by the removal of a 2-carbon progesterone by the removal of a 2-carbon

unit and hydroxylation at C-17unit and hydroxylation at C-17

EstradiolEstradiol is synthesized is synthesized from testosterone by th from testosterone by the removal of C-19 and fe removal of C-19 and formation of the aromatiormation of the aromati

c A ringc A ring

30. A hugh array of biomolecules, all call30. A hugh array of biomolecules, all called isoprenoids are synthesized using acted isoprenoids are synthesized using act

ivated isoprenesivated isoprenes

These include many pigments (carotenoids, phytol chain of chlorophylls), fragrant principles, vitamines (A, D, E, K), rubber, dolichols, quinones (ubiquinone, plastoquinone), juvenile hormones of insects.

Prenylation of proteins (attaching of geranylgeranyl and farnesyl groups) leads to membrane association.

Some Some plant pigmentsplant pigments are isoprenoids are isoprenoids

Some Some fragrant moleculesfragrant molecules are isoprenoids are isoprenoids (called (called terpenesterpenes))

Natural Natural rubberrubber is is ciscis-polyisoprene-polyisoprene

Isoprenoid tails functioIsoprenoid tails function to n to anchor proteinsanchor proteins to to

membranesmembranes

““Perfumes, colors and sPerfumes, colors and sounds echo one anotheounds echo one another.”r.”

Charles BaudelaireCharles BaudelaireCorrespondancesCorrespondances

SummarySummaryFatty acid biosynthesis takes a different pathway

from the reverse of its degradation and takes place in different cellular compartments.

The aceytl-CoA units are transported out of mitochondrial matrix as citrate.

Acetyl-CoA carboxylase catalyzes the rate-limiting step of fatty acid synthesis and is highly regulated by allosteric and covalent modifications.

Palmitate, the usual final product of fatty acid synthesis, can be further elongated and desaturated in sER.

Eicosanoids are derived from arachidonate by the action of cyclooxygenases and peroxidases.

Phosphatidic acid (diacylglycerol 3-phosphate) is the common precursor of both triacylglycerol and glycerophospholipids.

Glycerophospholipids are made using two alternative strategies of CDP modification.

The backbone of sphingolipids are made from palmitoyl-CoA and Ser.

Radioisotope tracer experiments revealed that all the 27 carbons of cholesterol are from acetyl-CoA.

The biosynthesis of cholesterol takes a long pathway, with the reaction catalyzed by HMG-CoA reductase being the rate-limiting step for de novo synthesis of cholesterol.

Activated isoprene untis, mevalonate, squalene were found to be important intermediates of cholesterol biosynthesis.

The lipids are transported as lipoprotein particles (including chylomicrons, VLDL, LDL, and HDL).

The de novo biosynthesis of cholesterol is regulated to complement the dietary uptake.

All streroid hormones are derived from choleterol.A huge arrays of isoprenoids are made using activa

ted isoprene units.