dr. wolf's chm 424 26- 1 chapter 26 lipids. dr. wolf's chm 424 26- 2 lipidslipids lipids...

Dr. Wolf's CHM 424 26- 1

Chapter 26Chapter 26LipidsLipids


LipidsLipids

Lipids are naturally occurring substances Lipids are naturally occurring substances grouped together on the basis of a common grouped together on the basis of a common property—they are more soluble in nonpolar property—they are more soluble in nonpolar solvents than in water.solvents than in water.

Some of the most important of them—the ones Some of the most important of them—the ones in this chapter—are related in that they have in this chapter—are related in that they have acetic acid (acetate) as their biosynthetic origin.acetic acid (acetate) as their biosynthetic origin.

In many biosynthetic pathways a substance In many biosynthetic pathways a substance called called acetyl coenzyme A acetyl coenzyme A serves as the source serves as the source of acetate.of acetate.


26.126.1Acetyl Coenzyme AAcetyl Coenzyme A


Structure of Coenzyme AStructure of Coenzyme A P

OP

ON N

SR

H3C CH3

OH

O O

H H

O

HO O O OH

O

HO

OPHO

HO

O

NN

NN

NH2

R = H; Coenzyme AR = H; Coenzyme A

R = CCHR = CCH33; Acetyl coenzyme A; Acetyl coenzyme A

OO


Reactivity of Coenzyme AReactivity of Coenzyme A

Nucleophilic acyl substitutionNucleophilic acyl substitution

CHCH33CCSCoASCoA

OOHHYY ••••

CHCH33CC

OO

YY •••• ++ HSCoAHSCoA

Acetyl coenzyme A is a source of an acetyl Acetyl coenzyme A is a source of an acetyl group toward biological group toward biological nucleophilesnucleophiles; it is an ; it is an acetyl transfer agent.acetyl transfer agent.


Reactivity of Coenzyme AReactivity of Coenzyme A

can react via enolcan react via enol

CHCH33CCSCoASCoA

OO

Acetyl coenzyme A reacts Acetyl coenzyme A reacts with biological with biological electrophileselectrophiles at its at its carbon atom.carbon atom.

CCSCoASCoA

OHOH

HH22CC

EE++

CHCH22CCSCoASCoA

OO

EE


26.226.2Fats, Oils, and Fatty AcidsFats, Oils, and Fatty Acids


Fats and OilsFats and Oils

Fats and oils are naturally occurring mixture of Fats and oils are naturally occurring mixture of triacylglycerols (also called triglycerides).triacylglycerols (also called triglycerides).

Fats are solids; oils are liquids.Fats are solids; oils are liquids.

RCOCHRCOCH

CHCH22OCR'OCR'OO

CHCH22OCR"OCR"

OO

OO


CHCH33(CH(CH22))1616CCOCHOCH

CHCH22OOC(CHC(CH22))1616CHCH33OO

CHCH22OOC(CHC(CH22))1616CHCH33

OO

OO


Tristearin; mp 72°CTristearin; mp 72°C



2-Oleyl-1,3-distearylglycerol; mp 43°C2-Oleyl-1,3-distearylglycerol; mp 43°C



OO

OO

CHCH22(CH(CH22))66CCOCHOCH

OO

CC

HH

CC

HH

CHCH33(CH(CH22))66CHCH22



2-Oleyl-1,3-distearylglycerol2-Oleyl-1,3-distearylglycerolmp 43°Cmp 43°C

HH22, Pt, Pt

TristearinTristearinmp 72°Cmp 72°C


OO

R'CR'COCHOCH

CHCH22OOCRCROO

CHCH22OOCR"CR"

OO

Fatty AcidsFatty Acids

Acids obtained by the hydrolysis of fats and oils are called Acids obtained by the hydrolysis of fats and oils are called fatty acids. fatty acids.

Fatty acids usually have an unbranched chain with an even Fatty acids usually have an unbranched chain with an even number of carbon atoms.number of carbon atoms.

If double bonds are present, they are almost always cis.If double bonds are present, they are almost always cis.

HH22OOHOCHHOCH

CHCH22OHOH

CHCH22OHOH

OO

HOCRHOCROO

R'COHR'COH

OO

HOCR"HOCR"


Table 26.1Table 26.1

OO

CHCH33(CH(CH22))1010COHCOH Dodecanoic acidDodecanoic acid Lauric acidLauric acid

Systematic nameSystematic name Common nameCommon name

OO

CHCH33(CH(CH22))1212COHCOH Tetradecanoic acidTetradecanoic acid Myristic acidMyristic acid

OO

CHCH33(CH(CH22))1414COHCOH Hexadecanoic acidHexadecanoic acid Palmitic acidPalmitic acid



OO

CHCH33(CH(CH22))1616COHCOH Octadecanoic acidOctadecanoic acid Stearic acidStearic acid

OO

CHCH33(CH(CH22))1818COHCOH Icosanoic acidIcosanoic acid Arachidic acidArachidic acid

Systematic nameSystematic name Common nameCommon name



OO

CC

HH

CC

HH

CHCH33(CH(CH22))77 (CH(CH22))77COHCOH

Systematic name: (Systematic name: (ZZ)-9-Octadecenoic acid)-9-Octadecenoic acid

Common name: Oleic acidCommon name: Oleic acid



Systematic name: (9Systematic name: (9ZZ, 12, 12ZZ)-9,12-Octadecadienoic acid)-9,12-Octadecadienoic acid

Common name: Linoleic acidCommon name: Linoleic acid

CC

HH

CC

HH

CHCH33(CH(CH22))44

OO

(CH(CH22))77COHCOHCHCH22

CC

HH

CC

HH



Systematic name: Systematic name: (9(9ZZ, 12, 12ZZ, 15, 15ZZ)-9,12,15-)-9,12,15-Octadecatrienoic acidOctadecatrienoic acid

Common name: Linolenic acidCommon name: Linolenic acid

CC

HH

CC

HH

OO

(CH(CH22))77COHCOHCHCH22

CC

HH

CC

HH

CHCH33CHCH22

CC

HH

CC

HH

CHCH22



Systematic name: Systematic name: (5Z, 8Z, 11(5Z, 8Z, 11ZZ, 14, 14ZZ)-5,8,11,14-)-5,8,11,14-Icosatetraenoic acidIcosatetraenoic acid

Common name: Arachidonic acidCommon name: Arachidonic acid

HH

HH HH

HH

HH HHHH

HH

OHOH

OO


trans-Fatty Acidstrans-Fatty Acids

Are formed by isomerization that can occur Are formed by isomerization that can occur when esters of cis-fatty acids are hydrogenated.when esters of cis-fatty acids are hydrogenated.

OO

OROR

HH OO

ORORHH

HH22, cat, cat


OO

OROR

HH OO

ORORHH

HH

OO

OROR

HH

HH22, cat, cat


26.326.3Fatty Acid BiosynthesisFatty Acid Biosynthesis


Fatty Acid BiosynthesisFatty Acid Biosynthesis

Fatty acids are biosynthesized via acetyl Fatty acids are biosynthesized via acetyl coenzyme A.coenzyme A.

The group of enzymes involved in the overall The group of enzymes involved in the overall process is called process is called fatty acid synthetasefatty acid synthetase..

One of the key components of fatty acid One of the key components of fatty acid synthetase is synthetase is acyl carrier protein acyl carrier protein (ACP—SH).(ACP—SH).



An early step in fatty acid biosynthesis is the An early step in fatty acid biosynthesis is the reaction of acyl carrier protein with acetyl reaction of acyl carrier protein with acetyl coenzyme A.coenzyme A.

CHCH33CCSCoASCoA

OO

++ HS—ACPHS—ACP CHCH33CCS—ACPS—ACP

OO

++ HHSCoASCoA



A second molecule of acetyl coenzyme A reacts A second molecule of acetyl coenzyme A reacts at its at its carbon atom with carbon dioxide (as carbon atom with carbon dioxide (as HCOHCO33

––) to give malonyl coenzyme A.) to give malonyl coenzyme A.

CHCH33CCSCoASCoA

OO

++ HCOHCO33

––

AcetylAcetylcoenzyme Acoenzyme A

OCOCCHCH22CCSCoASCoA

OO

––OO

MalonylMalonylcoenzyme Acoenzyme A



Malonyl coenzyme A then reacts with acyl Malonyl coenzyme A then reacts with acyl carrier protein.carrier protein.

OCOCCHCH22CCSCoASCoA

OO

––OO

MalonylMalonylcoenzyme Acoenzyme A

ACP—SHACP—SHOCOCCHCH22CCS—ACPS—ACP

OO

––OO



Malonyl—ACP and acetyl—ACP react by Malonyl—ACP and acetyl—ACP react by carbon-carbon bond formation, accompanied by carbon-carbon bond formation, accompanied by decarboxylation.decarboxylation.

CHCH22CCS—ACPS—ACP

OO––

OO

CCOO••••

••••••••

CHCH33CC S—ACPS—ACP

OO CHCH22CCS—ACPS—ACP

OO

CHCH33CC

OO

SS-Acetoacetyl—ACP-Acetoacetyl—ACP



In the next step, the ketone carbonyl is reduced In the next step, the ketone carbonyl is reduced to a secondary alcohol.to a secondary alcohol.


OO

CHCH33CC

OO

SS-Acetoacetyl—ACP-Acetoacetyl—ACP

NADPHNADPHCHCH22CCS—ACPS—ACP

OO

CHCH33CC

OHOH

HH



The alcohol then dehydrates.The alcohol then dehydrates.


OO

CHCH33CC

OHOH

HH

CHCCHCS—ACPS—ACP

OO

CHCH33CHCH



Repeating the process gives a 6-carbon acyl Repeating the process gives a 6-carbon acyl group, then an 8-carbon one, then 10, etc.group, then an 8-carbon one, then 10, etc.

CHCH33CHCH22CHCH22CCS—ACPS—ACP

OO

CHCCHCS—ACPS—ACP

OO

CHCH33CHCH

Reduction of the double bond yieldsReduction of the double bond yieldsACP bearing an attached butanoyl group.ACP bearing an attached butanoyl group.


26.426.4PhospholipidsPhospholipids


PhospholipidsPhospholipids

Phospholipids are intermediates in the Phospholipids are intermediates in the biosynthesis of triacylglycerols.biosynthesis of triacylglycerols.

The starting materials are The starting materials are LL-glycerol 3--glycerol 3-phosphate and the appropriate acyl coenzyme phosphate and the appropriate acyl coenzyme A molecules.A molecules.


CHCH22OPOOPO33HH22

CHCH22OHOH

HHHOHO ++ R'CR'CSCoASCoA

OO

RCRCSCoASCoA

OO

++

CHCH22OPOOPO33HH22

CHCH22OOCRCR

HHR'CR'COO

OO

OOThe diacylated The diacylated species formed species formed in this step is in this step is called a called a phosphatidic phosphatidic acidacid..

Dr. Wolf's CHM 424 26- 33CHCH22OPOOPO33HH22

CHCH22OOCRCR

HHR'CR'COO

OO

OOThe The phosphatidic phosphatidic acid then acid then undergoes undergoes hydrolysis of its hydrolysis of its phosphate ester phosphate ester function.function.

CHCH22OHOH

CHCH22OOCRCR

HHR'CR'COO

OO

OO

HH22OO


Reaction with a Reaction with a third acyl third acyl coenzyme A coenzyme A molecule yields molecule yields the the triacylglycerol.triacylglycerol.

CHCH22OHOH

CHCH22OOCRCR

HHR'CR'COO

OO

OO

R"CSCoAR"CSCoA

OO

CHCH22OCR"OCR"

CHCH22OOCRCR

HHR'CR'COO

OO

OO

OO


CHCH22OPOOPO33HH22

CHCH22OOCRCR

HHR'CR'COO

OO

OO

Phosphatidic acids are intermediates in the Phosphatidic acids are intermediates in the formation of formation of phosphatidylcholinephosphatidylcholine..

PhosphatidylcholinePhosphatidylcholine

CHCH22OPOOPO22

CHCH22OOCRCR

HHR'CR'COO

OO

OO

––

(CH(CH33))33NCHNCH22CHCH22OO++



CHCH22OPOOPO22

CHCH22OOCRCR

HHR'CR'COO

OO

OO

––

(CH(CH33))33NCHNCH22CHCH22OO++

polar "head group"polar "head group"

hydrophobic "tail"hydrophobic "tail"

hydrophobic "tail"hydrophobic "tail"



hydrophilic "head group"hydrophilic "head group"

hydrophobichydrophobic(lipophilic) "tails"(lipophilic) "tails"


Cell MembranesCell Membranes

Cell membranes are Cell membranes are "lipid bilayers." Each "lipid bilayers." Each layer has an assembly layer has an assembly of phosphatidyl of phosphatidyl choline molecules as choline molecules as its main structural its main structural component.component.

waterwater

waterwater


Cell MembranesCell Membranes

The interior of the cell The interior of the cell membrane is membrane is hydrocarbon-like. hydrocarbon-like. Polar materials cannot Polar materials cannot pass from one side to pass from one side to the other of the the other of the membrane.membrane.

waterwater

waterwater


26.526.5WaxesWaxes


WaxesWaxes

Waxes are water-repelling solids that coat the Waxes are water-repelling solids that coat the leaves of plants, etc.leaves of plants, etc.

Structurally, waxes are mixtures of esters. The Structurally, waxes are mixtures of esters. The esters are derived from fatty acids and long-esters are derived from fatty acids and long-chain alcohols.chain alcohols.

CHCH33(CH(CH22))1414COCHCOCH22(CH(CH22))2828CHCH33

OO

Triacontyl hexadecanoate: occurs in beeswaxTriacontyl hexadecanoate: occurs in beeswax


26.626.6ProstaglandinsProstaglandins


ProstaglandinsProstaglandins

Prostaglandins are involved in many biological Prostaglandins are involved in many biological processes.processes.

Are biosynthesized from linoleic acid (CAre biosynthesized from linoleic acid (C1818) via ) via

arachidonic acid (Carachidonic acid (C2020). (See Table 26.1)). (See Table 26.1)


Examples: PGEExamples: PGE1 1 and PGFand PGF11 OO

HOHO

OO

OHOH

OHOH HOHO

HOHO OHOH

OO

OHOH

PGEPGE11

PGFPGF11


Prostaglandin BiosynthesisProstaglandin Biosynthesis

PGEPGE22 is biosynthesized from arachidonic acid is biosynthesized from arachidonic acid

The oxygens come from OThe oxygens come from O22

The enzyme involved (prostaglandin endoperoxide The enzyme involved (prostaglandin endoperoxide synthase) has cyclooxygenase (COX) acitivitysynthase) has cyclooxygenase (COX) acitivity



Arachidonic acidArachidonic acid

OO22

fatty acid cyclooxygenasefatty acid cyclooxygenase

COCO22HH

CHCH33

PGGPGG22

OO

HOOHOO

COCO22HH

CHCH33

OO



reduction ofreduction ofhydroperoxidehydroperoxide

PGGPGG22

OO

HOOHOO

COCO22HH

CHCH33

OO

PGHPGH22

OO

HOHO

COCO22HH

CHCH33

OO



OOHOHO HOHO

COCO22HH

CHCH33 PGEPGE22

PGHPGH22

OO

HOHO

COCO22HH

CHCH33

OO


IcosanoidsIcosanoids

Icosanoids include:Icosanoids include:prostaglandinsprostaglandins

thromboxanesthromboxanesprostacyclinsprostacyclins

leukotrienesleukotrienes

Icosanoids are compounds related to icosanoic acidIcosanoids are compounds related to icosanoic acidCHCH33(CH(CH22))1818COCO22H.H.


Thromboxane AThromboxane A22 (TXA (TXA22))

PGHPGH22

OO

HOHO

COCO22HH

CHCH33

OO

TXATXA22

OO

OOHOHO

COCO22HH

CHCH33

Thromboxane AThromboxane A22 is biosynthesized from PGH is biosynthesized from PGH22

TXATXA22 promotes platelet promotes platelet

aggregation and blood clottingaggregation and blood clotting

TXATXA22 promotes platelet promotes platelet

aggregation and blood clottingaggregation and blood clotting


Prostacyclin IProstacyclin I22 (PGI (PGI22))

PGIPGI22

Like thromboxane ALike thromboxane A22, prostacyclin I, prostacyclin I22 is is

biosynthesized from PGHbiosynthesized from PGH22

PGIPGI22 inhibits platelet inhibits platelet

aggregation and relaxesaggregation and relaxescoronary arteriescoronary arteries

PGIPGI22 inhibits platelet inhibits platelet

aggregation and relaxesaggregation and relaxescoronary arteriescoronary arteries

OHOH

HOHO22CC

CHCH33

HOHO

OO


Leukotriene CLeukotriene C44 (LTC (LTC44))

Leukotrienes arise from arachidonic acid viaLeukotrienes arise from arachidonic acid viaa different biosynthetic pathway. They are thea different biosynthetic pathway. They are thesubstances most responsible for constrictingsubstances most responsible for constrictingbronchial passages during asthma attacks.bronchial passages during asthma attacks.


Leukotriene CLeukotriene C44 (LTC (LTC44))

COCO22HH

OHOH

CHCH33

SSCHCH22CHCNHCHCHCNHCH22COCO22HH

OO

NHNH

CC OOOO22CCHCHCCHCH22CHCH22

NHNH33++

––


26.726.7Terpenes: The Isoprene RuleTerpenes: The Isoprene Rule


TerpenesTerpenes

Terpenes are natural products that are Terpenes are natural products that are structurally related to isoprene.structurally related to isoprene.

HH22CC CC

CHCH33

CHCH CHCH22

oror

IsopreneIsoprene(2-methyl-1,3-butadiene)(2-methyl-1,3-butadiene)


TerpenesTerpenes

Myrcene Myrcene (isolated from oil of bayberry) (isolated from oil of bayberry) is a typical terpene.is a typical terpene.

CHCH22

CHCH33

CHCH33CC CHCHCHCH22CHCH22CCHCCH

CHCH22 oror


The Isoprene UnitThe Isoprene Unit

An isoprene unit is the carbon skeleton of An isoprene unit is the carbon skeleton of isoprene (ignoring the double bonds)isoprene (ignoring the double bonds) Myrcene contains two isoprene units.Myrcene contains two isoprene units.


The Isoprene UnitThe Isoprene Unit

The isoprene units of myrcene are joined "head-The isoprene units of myrcene are joined "head-to-tail."to-tail." headhead tailtail

tailtail headhead



ClassClass Number of carbon atomsNumber of carbon atoms

MonoterpeneMonoterpene 1010

SesquiterpeneSesquiterpene 1515

DiterpeneDiterpene 2020

SesterpeneSesterpene 2525

TriterpeneTriterpene 3030

TetraterpeneTetraterpene 4040

Classification of TerpenesClassification of Terpenes


Figure 26.6Figure 26.6

Representative MonoterpenesRepresentative Monoterpenes -Phellandrene-Phellandrene

(eucalyptus)(eucalyptus)MentholMenthol

(peppermint)(peppermint)CitralCitral

(lemon grass)(lemon grass)

OO

HH

OHOH



Representative MonoterpenesRepresentative Monoterpenes -Phellandrene-Phellandrene

(eucalyptus)(eucalyptus)MentholMenthol

(peppermint)(peppermint)CitralCitral

(lemon grass)(lemon grass)

OO

HH

OHOH



Representative MonoterpenesRepresentative Monoterpenes

-Phellandrene-Phellandrene(eucalyptus)(eucalyptus)

MentholMenthol(peppermint)(peppermint)

CitralCitral(lemon grass)(lemon grass)



Representative SesquiterpenesRepresentative Sesquiterpenes

-Selinene-Selinene(celery)(celery)

HH





HH



Representative DiterpenesRepresentative Diterpenes

Vitamin AVitamin A

OHOH




Vitamin AVitamin A

OHOH




Vitamin AVitamin A



Representative TriterpeneRepresentative Triterpene

SqualeneSqualene(shark liver oil)(shark liver oil)

tail-to-tail linkage of isoprene unitstail-to-tail linkage of isoprene units


26.826.8Isopentenyl Pyrophosphate:Isopentenyl Pyrophosphate:The Biological Isoprene UnitThe Biological Isoprene Unit


The Biological Isoprene UnitThe Biological Isoprene Unit

The isoprene units in terpenes do not come from The isoprene units in terpenes do not come from isoprene.isoprene.

They come from isopentenyl pyrophosphate.They come from isopentenyl pyrophosphate.

Isopentenyl pyrophosphate (5 carbons) comes Isopentenyl pyrophosphate (5 carbons) comes from acetate (2 carbons) via mevalonate (6 from acetate (2 carbons) via mevalonate (6 carbons).carbons).


The Biological Isoprene UnitThe Biological Isoprene Unit

CHCH33COHCOH

OO

33 HOCCHHOCCH22CCHCCH22CHCH22OHOH

CHCH33

OHOH

OO

Mevalonic acidMevalonic acid

HH22CC CCHCCH22CHCH22OPOPOHOPOPOH

CHCH33 OO OO

Isopentenyl Isopentenyl pyrophosphatepyrophosphate


Isopentenyl PyrophosphateIsopentenyl Pyrophosphate


CHCH33 OO OO


oror

OPPOPP


Isopentenyl and Dimethylallyl PyrophosphateIsopentenyl and Dimethylallyl Pyrophosphate

Isopentenyl pyrophosphate is interconvertible withIsopentenyl pyrophosphate is interconvertible with2-methylallyl pyrophosphate.2-methylallyl pyrophosphate.

OPPOPP

OPPOPP

Dimethylallyl pyrophosphate has a leaving Dimethylallyl pyrophosphate has a leaving group (pyrophosphate) at an allylic carbon; it is group (pyrophosphate) at an allylic carbon; it is reactive toward nucleophilic substitution at this reactive toward nucleophilic substitution at this position.position.

Isopentenyl pyrophosphateIsopentenyl pyrophosphate Dimethylallyl pyrophosphateDimethylallyl pyrophosphate


26.926.9Carbon-Carbon Bond Formation Carbon-Carbon Bond Formation

in Terpene Biosynthesisin Terpene Biosynthesis


Carbon-Carbon Bond FormationCarbon-Carbon Bond Formation

The key process involves the double bond of The key process involves the double bond of isopentenyl isopentenyl pyrophosphatepyrophosphate acting as a nucleophile acting as a nucleophile toward the allylic carbon of dimethylallyl toward the allylic carbon of dimethylallyl pyrophosphatepyrophosphate..

++OPPOPP

OPPOPP


Carbon-Carbon Bond FormationCarbon-Carbon Bond Formation

++OPPOPP

OPPOPP––

++OPPOPP

OPPOPP


After C—C Bond Formation...After C—C Bond Formation...

++

OPPOPP

The carbocation The carbocation can lose a proton can lose a proton to give a double to give a double bond.bond.

OPPOPP

HH––++


After C—C Bond Formation...After C—C Bond Formation... OPPOPP

This compound is called geranyl pyrophosphate. It This compound is called geranyl pyrophosphate. It can undergo hydrolysis of its pyrophosphate to give can undergo hydrolysis of its pyrophosphate to give geraniol (rose oil).geraniol (rose oil).


After C—C Bond Formation...After C—C Bond Formation... OPPOPP OHOH

GeraniolGeraniol

HH22OO


From 10 Carbons to 15From 10 Carbons to 15 ++

OPPOPP

OPPOPP

Geranyl pyrophosphateGeranyl pyrophosphate

++OPPOPP


From 10 Carbons to 15From 10 Carbons to 15

++OPPOPP

HH––++

OPPOPP


From 10 Carbons to 15From 10 Carbons to 15 OPPOPP

This compound is called farnesyl This compound is called farnesyl pyrophosphate.pyrophosphate.

Hydrolysis of the pyrophosphate ester gives the Hydrolysis of the pyrophosphate ester gives the alcohol farnesol (Figure 26.6).alcohol farnesol (Figure 26.6).


From 15 Carbons to 20From 15 Carbons to 20 OPPOPP

Farnesyl pyrophosphate is extended by another Farnesyl pyrophosphate is extended by another isoprene unit by reaction with isopentenyl isoprene unit by reaction with isopentenyl pyrophosphate.pyrophosphate.

OPPOPP


CyclizationCyclization

Rings form by intramolecular carbon-carbon Rings form by intramolecular carbon-carbon bond formation.bond formation.

OPPOPP

OPPOPP

++

EE double double bondbond

ZZ double double bondbond


++

OHOH

HH––++

HH22OO

LimoneneLimonene

-Terpineol-Terpineol


Bicyclic TerpenesBicyclic Terpenes ++

++

++

-Pinene-Pinene

++

-Pinene-Pinene


26.1026.10The Pathway from Acetate to The Pathway from Acetate to Isopentenyl PyrophosphateIsopentenyl Pyrophosphate


RecallRecall

CHCH33COHCOH

OO

33 HOCCHHOCCH22CCHCCH22CHCH22OHOH

CHCH33

OHOH

OO



CHCH33 OO OO



Biosynthesis of Mevalonic AcidBiosynthesis of Mevalonic Acid

CHCH33CCHCCH22CSCoACSCoA

OOOO

SS-Acetoacetyl-Acetoacetylcoenzyme Acoenzyme A

In a sequence analogous to the early steps of In a sequence analogous to the early steps of fatty acid biosynthesis, acetyl coenzyme A is fatty acid biosynthesis, acetyl coenzyme A is converted to converted to SS-acetoacetyl coenzyme A.-acetoacetyl coenzyme A.



CHCH33CSCoACSCoA

OO

++CHCH33CCHCCH22CSCoACSCoA

OOOO

In the next step, S-acetoacetyl coenzyme A In the next step, S-acetoacetyl coenzyme A reacts with acetyl coenzyme A.reacts with acetyl coenzyme A.

Nucleophilic addition of acetyl coenzyme A Nucleophilic addition of acetyl coenzyme A (probably via its enol) to the ketone carbonyl of (probably via its enol) to the ketone carbonyl of S-S-acetoacetyl coenzyme A occurs.acetoacetyl coenzyme A occurs.



CHCH33CSCoACSCoA

OO

CHCH33CCCHCH22CSCoACSCoA

CHCH22COHCOH

HOHO OO

OO

++CHCH33CCHCCH22CSCoACSCoA

OOOO




CHCH22COHCOH

HOHO OO

OO

Next, the Next, the acyl coenzyme A acyl coenzyme A function is reduced.function is reduced.

The product of this reduction is mevalonic acid.The product of this reduction is mevalonic acid.



CHCH22COHCOH

HOHO OO

OO

CHCH33CCCHCH22CHCH22OHOH

CHCH22COHCOH

HOHO

OO

MevalonicMevalonicacidacid


Conversion of Mevalonic Acid to Conversion of Mevalonic Acid to Isopentenyl PyrophosphateIsopentenyl Pyrophosphate

CHCH33CCHCCH22CHCH22OOHH

CHCH22COHCOH

HHOO

OO

The two hydroxyl groups of mevalonic acid The two hydroxyl groups of mevalonic acid undergo phosphorylation.undergo phosphorylation.

CHCH33CCHCCH22CHCH22OOPPPP

CHCH22COHCOH

OO

OOPOPO33

2–2–



Phosphorylation is followed by a novel Phosphorylation is followed by a novel elimination involving loss of COelimination involving loss of CO22 and PO and PO44

3–3–..


CHCH22

OO

OOPOPO33

2–2–

CC OO••••

••••••••––


CHCH22

OOPOPO33

3–3–

OO CC OO



The product of this elimination is isopentenyl The product of this elimination is isopentenyl pyrophosphate.pyrophosphate.


CHCH22


Biosynthetic pathway is based on Biosynthetic pathway is based on experiments with experiments with 1414C-labeled acetateC-labeled acetate

CCHH33COHCOH

OO

HOCHOCCCHH22CCCCHH22CHCH22OHOH

CCHH33

OHOH

OO


HH22CC CCCCHH22CHCH22OPOPOHOPOPOH

CCHH33 OO OO



Biosynthetic pathway is based on Biosynthetic pathway is based on experiments with experiments with 1414C-labeled acetateC-labeled acetate

CCHH33COHCOH

OO

Citronellal biosynthesized using Citronellal biosynthesized using 1414C-labeled C-labeled acetate as the carbon source had the labeled acetate as the carbon source had the labeled carbons in the positions indicated.carbons in the positions indicated.

HH22CC CCCCHH22CHCH22OPOPOHOPOPOH

CCHH33 OO OO OO

HH

••

•• •• ••

••

••

Dr. Wolf's CHM 424 26- 100

26.1126.11Steroids: CholesterolSteroids: Cholesterol

Dr. Wolf's CHM 424 26- 101

Structure of CholesterolStructure of Cholesterol Fundamental framework of steroids is the Fundamental framework of steroids is the tetracyclic unit shown.tetracyclic unit shown.

Dr. Wolf's CHM 424 26- 102

Structure of CholesterolStructure of Cholesterol

Cholesterol has the fundamental steroid Cholesterol has the fundamental steroid skeleton modified as shown.skeleton modified as shown.

HOHO

CHCH33

HH

HH

HH

CHCH33

CHCH33 CHCH33

CHCH33

Dr. Wolf's CHM 424 26- 103

Structure of CholesterolStructure of Cholesterol

Some parts of the cholesterol molecule are Some parts of the cholesterol molecule are isoprenoid. But other parts don't obey the isoprenoid. But other parts don't obey the isoprene rule. Also, cholesterol has 27 carbons, isoprene rule. Also, cholesterol has 27 carbons, which is not a multiple of 5.which is not a multiple of 5.

HOHO

CHCH33

HH

HH

HH

CHCH33

CHCH33 CHCH33

CHCH33

Dr. Wolf's CHM 424 26- 104

Biosynthesis of CholesterolBiosynthesis of Cholesterol

Cholesterol is biosynthesized from the triterpene Cholesterol is biosynthesized from the triterpene squalene. In the first step, squalene is squalene. In the first step, squalene is converted to its 2,3-epoxide.converted to its 2,3-epoxide. OO

OO22, NADH, enzyme, NADH, enzyme

Dr. Wolf's CHM 424 26- 105


To understand the second step, we need to look To understand the second step, we need to look at squalene oxide in a different conformation, at squalene oxide in a different conformation, one that is in a geometry suitable for cyclization.one that is in a geometry suitable for cyclization.

OO

OO

Dr. Wolf's CHM 424 26- 106


Cyclization is triggered by epoxide ring opening.Cyclization is triggered by epoxide ring opening. OO

HH++

++

HOHO

HH

Dr. Wolf's CHM 424 26- 107


The five-membered ring expands to a six-membered The five-membered ring expands to a six-membered one.one.

++

HOHO

HH

HH

+

HOHO

HH

Dr. Wolf's CHM 424 26- 108


Cyclization to form a tetracyclic carbocation.Cyclization to form a tetracyclic carbocation.

HH

+

HOHO

HH

+

HH

HH

HOHO

protosteryl cationprotosteryl cation

Dr. Wolf's CHM 424 26- 109


Deprotonation and multiple migrations.Deprotonation and multiple migrations.

H

+HOHO

OHOH22

••••••••

HH

HH HOHO

HH

HH

Dr. Wolf's CHM 424 26- 110


The product of this rearrangement is a The product of this rearrangement is a triterpene called lanosterol. A number of triterpene called lanosterol. A number of enzyme-catalyzed steps follow that convert enzyme-catalyzed steps follow that convert lanosterol to cholesterol.lanosterol to cholesterol.

HOHO

HH

HH

Dr. Wolf's CHM 424 26- 111

CholesterolCholesterol

Cholesterol is the biosynthetic precursor to a Cholesterol is the biosynthetic precursor to a large number of important steroids:large number of important steroids:

Bile acidsBile acidsVitamin DVitamin DCorticosteroidsCorticosteroidsSex hormonesSex hormones

Dr. Wolf's CHM 424 26- 112

26.1226.12Vitamin DVitamin D

Dr. Wolf's CHM 424 26- 113

CholesterolCholesterol HOHO

CHCH33

HH

HH

HH

CHCH33

CHCH33 CHCH33

CHCH33

Cholesterol is the precursor to vitamin D.Cholesterol is the precursor to vitamin D.

Enzymes dehydrogenate cholesterol to introduce a second Enzymes dehydrogenate cholesterol to introduce a second double bond in conjugation with the existing one. The double bond in conjugation with the existing one. The product of this reaction is called 7-dehydrocholesterol.product of this reaction is called 7-dehydrocholesterol.

Dr. Wolf's CHM 424 26- 114

7-Dehydrocholesterol7-Dehydrocholesterol

HOHO

CHCH33

HH HH

CHCH33

CHCH33 CHCH33

CHCH33

Sunlight converts 7-dehydrocholesterol on the Sunlight converts 7-dehydrocholesterol on the skin's surface to vitamin Dskin's surface to vitamin D33..

Dr. Wolf's CHM 424 26- 115

Vitamin DVitamin D33

CHCH33

HOHO

HH

CHCH33 CHCH33

CHCH33

Insufficient sunlight can lead to a deficiency of Insufficient sunlight can lead to a deficiency of vitamin Dvitamin D33, interfering with Ca, interfering with Ca2+2+ transport and transport and

bone development. Rickets can result.bone development. Rickets can result.

Dr. Wolf's CHM 424 26- 116

26.1326.13Bile AcidsBile Acids

Dr. Wolf's CHM 424 26- 117


CHCH33

HH

HH

HH

CHCH33

CHCH33 CHCH33

CHCH33

Oxidation in the liver degrades the cholesterol side chain Oxidation in the liver degrades the cholesterol side chain and introduces OH groups at various positions on the and introduces OH groups at various positions on the steroid skeleton. Cholic acid (next slide) is the most steroid skeleton. Cholic acid (next slide) is the most abundant of the bile acids.abundant of the bile acids.

Dr. Wolf's CHM 424 26- 118

Cholic AcidCholic Acid

Salts of cholic acid amides (Salts of cholic acid amides (bile saltsbile salts), such as sodium ), such as sodium taurocholate (next slide), act as emulsifying agents to aid taurocholate (next slide), act as emulsifying agents to aid digestion. digestion.

HHOO

CHCH33

HH

HH

HH

CHCH33

CHCH33

HHOOHH

HHOO

OO

OHOH

Dr. Wolf's CHM 424 26- 119

Sodium TaurocholateSodium Taurocholate HHOO

CHCH33

HH

HH

HH

CHCH33

CHCH33

HHOOHH

HHOO

OO

NHCHNHCH22CHCH22SOSO33NaNa

Dr. Wolf's CHM 424 26- 120

26.1426.14CorticosteroidsCorticosteroids

Dr. Wolf's CHM 424 26- 121


CHCH33

HH

HH

HH

CHCH33

CHCH33 CHCH33

CHCH33

Enzymatic degradation of the side chain and oxidation of Enzymatic degradation of the side chain and oxidation of various positions on the steroid skeleton convert cholesterol various positions on the steroid skeleton convert cholesterol to to corticosteroidscorticosteroids. .

Dr. Wolf's CHM 424 26- 122

CortisolCortisol

Cortisol is the most abundant of the corticosteroids. Enzyme-Cortisol is the most abundant of the corticosteroids. Enzyme-catalyzed oxidation of cortisol gives cortisone.catalyzed oxidation of cortisol gives cortisone.

OO

CHCH33

HH

HH

HH

CHCH33OOHH

HHOO

OO

OOHH

Dr. Wolf's CHM 424 26- 123

CortisoneCortisone

Corticosteroids are involved in maintaining electrolyte Corticosteroids are involved in maintaining electrolyte levels, in the metabolism of carbohydrates, and in levels, in the metabolism of carbohydrates, and in mediating the allergic response.mediating the allergic response.

OO

CHCH33

HH

HH

HH

CHCH33OOHH

OO

OO

OOHH

Dr. Wolf's CHM 424 26- 124

26.1526.15Sex HormonesSex Hormones

Dr. Wolf's CHM 424 26- 125

TestosteroneTestosterone

Testosterone is the main male sex hormone. Testosterone is the main male sex hormone.

OO

HH

HH

HH

HH33CC

HH33CCOHOH

Dr. Wolf's CHM 424 26- 126

EstradiolEstradiol

Estradiol is a female sex hormone involved in Estradiol is a female sex hormone involved in regulating the menstrual cycle and in reproduction. regulating the menstrual cycle and in reproduction.

HOHO

HH

HH

HH

HH33CCOHOH

Dr. Wolf's CHM 424 26- 127

ProgesteroneProgesterone

Supresses ovulation during pregnancy. Supresses ovulation during pregnancy.

OO

HH

HH

HH

HH33CC

HH33CCOO

Dr. Wolf's CHM 424 26- 128

26.1626.16CarotenoidsCarotenoids

Dr. Wolf's CHM 424 26- 129

CarotenoidsCarotenoids

Carotenoids are naturally occurring pigments.Carotenoids are naturally occurring pigments.

Structurally, carotenoids are tetraterpenes. Structurally, carotenoids are tetraterpenes. They have 40 carbons. Two CThey have 40 carbons. Two C2020 units are linked units are linked

in a tail-to-tail fashion.in a tail-to-tail fashion.

Examples are lycopene and Examples are lycopene and -carotene.-carotene.

Dr. Wolf's CHM 424 26- 130

CarotenoidsCarotenoids

Lycopene (tomatoes)Lycopene (tomatoes) -Carotene (carrots)-Carotene (carrots)

Dr. Wolf's CHM 424 26- 131

End of Chapter 26End of Chapter 26

dr. wolf's chm 424 26- 1 chapter 26 lipids. dr. wolf's chm 424 26- 2 lipidslipids lipids...

Documents

cscoa o acetyl coenzyme

o slide

reactivity of coenzyme

h coenzyme

structure of coenzyme

cscoa oe slide

acetyl group

c o y hscoa acetyl coenzyme