Lipid Metabolism

Major roles of lipids in cell structure and metabolism:

triacylglycerols: major form of stored energy in mammals
phospholipids, glycolipids, cholesterol: components of cell membranes
cholesterol: precursor of steroid hormones and bile salts
hormones and intracellular messengers: prostaglandins, prostacyclins,
thromboxanes, leucotrienes, lipoxins
protein targeting to membranes

Fatty Acid Metabolism

Fatty acids have 4 major physiological roles:
components of phospholipids and glycolipids
covalent attachment to proteins, protein targeting
fuel and storage (triglycerides)
hormones and intracellular messengers

Note: double bonds when present are cis

and unconjugated.

Triacylglycerols, stored in adapose cells, are the major energy reserve in animals

O
CH2
CH2

OH

CH2

OH

Glycerol

R1
Fats provide about 6 times
the energy/mass of carbohydrates

OH

CH

CH
CH2

O
O

C
O

R2

R3

Triacylglycerol

Stored in an anhydrous state

carbon atoms have low oxidation states

Comparison of fatty acid biosynthesis and degradation

Digestion of dietary lipids: emulsification with detergents

Major bile acids and their glycine and taurine conjugates

Bile acids: synthesized in liver, passed to gall bladder, secreted into

small intestine, re-adsorbed, taken up by liver.
The fraction that escape re-adsorption is the only route for cholesterol excretion.
If bile acid production is defective due to liver disease, large amounts of fats
are excreted into the feces (steatorrhea).

Dietary lipids are digested by pancreatic lipases

pancreatic lipase-colipase complex
triacylglycerol-------> 1,2 diacylglycerol---------->2 acylglycerol
interfacial activation: The enzyme is only
active in complex with micelles.

Phospholipids are degraded by pancreatic phospholipases

hypothetical model

Active site and catalytic mechanism of phospholipase A2

cut-away view of active site with tetrahedral transition

state analogue MJ33.

Bound Ca2+ participates in activation of reactive H20

and stabilizes oxyanion of transition state.

Bile salts micells with dispersion/digestion products and lipid-soluble

vitamins are taken up by the cells of the intestinal mucosa

Inside the cells of the intestinal mucosa,

fatty acids are converted back to
triacylglycerols and packaged into
chylomicrons along with cholesterol and
vitamins.
Chylomicrons are released into lymphatic
system and from there into the blood stream.

rat fatty acid binding protein bound to palmitate.

a beta clam

Cartoon of the LDL particle

Glycerol from the breakdown of dietary and endogenous triacylglycerols

is transported to the liver and used in glycolysis and gluconeogenesis

Fatty acids released from adipose tissue is carried in the

bloodstream by serum albumin

The synthesis and degredation of

triacylglycerols by the adipose tissue is
hormonally regulated.
Fatty acids are released into the
bloodstream in complex with serum
albumin.
Serum albumin carrys a variety of
insoluble molecules, including
fatty acids, hormones, drugs.

human serum albumin in complex with 7 palmitate

Sites of regulation of fatty acid metabolism

The utilization of stored triacylglycerols requires three stages of processing

1. Hormone-sensitive lipase of adapose tissue liberates fatty acids,
that are carried in the blood by serum albumin.
2. At the consuming tissues, fatty acids are activated and transported
into the mitochondrion for degradation.
3. In the mitochondrion, fatty acids are broken down in a step-wise
fashion to form acetyl~CoA, which is used in the TCA cycle.

Fatty acid activation on the ER or outer mitochondrial membrane

There are at least three different acyl-CoA

synthetases in humans, that act on FA of different
chain length.
FA + CoA + ATP <=> acyl~CoA + AMP + PPi
Reaction is driven in the forward direction by
hydrolysis of PPi.
The acyl adenylylate is held tightly by the enzyme.
mechanism demonstrated by Paul Berg
Acyl adenylates are frequently formed when
carboxyl groups are activated in biochemical
reactions.

Figure 25-9 Mechanism of fatty acid activation catalyzed

Carnitine carries long-chain activated fatty acids into the mitochondrial matrix

Figure 25-10 Acylation of carnitine catalyzed by carnitine palmitoyltransferase.

The equilibrium constant for this reaction is about 1. Normally, transfer of acyl group from
an alcohol to a sulfhydryl group is thermodynamically unfavorable. Why does the O-acyl
group in carnitine have such a high group transfer potential?

Acetyl~CoA, NADH, and FADH2 are generated in each

round of fatty acid oxidation

-oxidation

1. Acyl~CoA dehydrogenase (AD) (4 different)

formation of trans double bond
deficiency-> SIDS, also-dont eat ackee fruit!
2. enoyl hydratase (EH)
hydration of trans double bond to form 3-Lhydroxyacyl-CoA
(cis->D)
3. 3-L-hydroxyacyl-CoA dehydrogenase (HAD)
oxidation to the -keto
4. ketoacyl thiolase (KT)
cleavage of the bond to release acetyl-CoA and
shortened acyl-CoA
Notes
First 3 steps resemble succinate->->->OAA in TCA cycle.
Electron transfer flavoprotein (ETF) connects AD to mitochondrial
electron transport chain. (actual yeild ~ 1.5 ATP)
Steps 2, 3, and 4 by trifunctional proteins

AD reaction: Glu376 extracts a proton from C, FAD extracts a hydride ion equivalent from C

Figure 25-13 Ribbon diagram of the active site region in a subunit of

medium-chain acyl-CoA dehydrogenase from pig liver mitochondria in
complex with octanoyl-CoA.

Dont eat unripe ackee fruit

Figure 25-14 Metabolic conversions of hypoglycin A to yield a product that inactivates

acyl-CoA dehydrogenase.

Note: mechanism-based inhibitor, first step of the reaction creates the inhibitor,
covalent modification of flavin kills enzyme

The thiolase reaction involves an enzyme thioester intermediate

Note: acetyl-CoA carbanion as in the first step of

the citrate synthase reaction.

Figure 25-15

Mechanism of action of -ketoacyl-CoA thiolase.

The complete oxidation of palmitate yeilds ~106 molecules of ATP

Palmitoyl~CoA is C16-acyl CoA
There will be 7 turns of the cycle, with the final turn generating 2 acetyl~CoA.
palmitoyl~CoA + 7 FAD + 7 NAD+ + 7 CoA---> 8 acetyl~CoA + 7 FADH2 + 7 NADH + 7 H+
7 NADH X 2.5 ATP/NADH-----------------> 17.5 ATP
7 FADH2 X 1.5 ATP/FADH2--------------->10.5 ATP
8 acetyl~CoA X 10ATP/acetyl~CoA------->80 ATP
Total--------------------------------------------108 ATP
activation of palmitate-------------------->
Yeild

-2 ATP
106 ATP

Fatty acids are also oxidized in peroxisomes

Peroxisomal -oxidation in animals serves to shorten very long chain fatty acids
(>C22) to octanyl~CoA.
The ALD protein transports very long chain fatty acids into the peroxisome. Defect is X-ALD,
X-Adrenoleucodystrophy, very long chain fatty acids accumulate and destroy myelin. Usually
fatal by age 10.
Zellweger syndrome-defective peroxisomes, defect in transporting enzymes into peroxisomes.
Liver, kidney, and muscle abnormalities and usually fatal by age 6.
First enzyme of the peroxisomal pathway is acyl~CoA oxidase; electrons are transferred
directly to O2, so process is less efficient than oxidation in mitochondrion.
Acyl~CoA products of partial peroxisomal oxidation are converted to carnitine esters for
complete oxidation in the mitochondtion.

Certain fatty acids require additional steps for degredation

Three isomerases and a reductase are required for the oxidation of
unsaturated fatty acids.
Odd chain fatty acids yeild propionyl~CoA, which is converted into
succinyl~CoA in a reaction that requires vitamin B12.
Branched chain fatty acids with the branch at odd-number carbons undergo
oxidation.

a branched chain fatty acid

Fig 25-16. Two common

unsaturated fatty acids.

produced in the oxidation of isoleucine, valine,

methionine, and odd chain fatty acids

Three isomerases and a reductase permit oxidation of unsaturated FA

1. enoyl-CoA isomerase creates substrate for EH
2. reductase and 3,2 enoyl isomerase create
substrate for EH
3. The 3,2 isomerase is reversible. 2,5 is occasionally
converted to 3,5; 3,5-2,4 isomerase creates the
substrate for reductase.

Formation of Succinyl~CoA from Propionyl~CoA involves addition of a

one-carbon unit and rearrangement of the carbon skeleton.

Biotin-containing enzyme

probably via resonance-stabilized carbanion

coenzyme B12 prosthetic group

Review of 1 carbon metabolism

One carbon groups are carried by biotin (CO2), by tetrahydrofolate (THF) and by Sadenosylmethionine (SAM, adoMet). In addition, one carbon units are carried by
methylcobalamin (shown later).
Biotin is involved in carboxylations as in pyruvate carboxylase. SAM is a major
methyl donor, due to its high transfer potential. Example, methylation of proteins .
THF is used in a wide variety of biosynthetic reactions. Mammals cannot synthesize
folate, which is obtained from the diet or intestinal microorganisms. DHFR catalyzes
both steps of the reduction of folic acid to THF.

Mechanism of the propionyl~CoA carboxylase reaction

Notes:
1. The two reactions occur at separate active sites on the enzyme; the biotin swings between the sites.
2. Formation of the C2 carbanion, proton to thioester is removed in 2nd reaction.

Coenzyme B12 (cobalamin) is involved in free radical reactions and methyl

transfer reactions
This figure shows the adenosylcobalamin
form of coenzyme B12, which is involved
in free radical reactions.
B12 is synthesized by microorganisms , but
not by plants or animals.
Pernicious anemia is a deficiency in B12.
It is characterized by low number of RBC,
low hemoglobin production, and
progressive neurological deterioration.
Uptake in the gut involves a specialized
glycoprotein known as intrinsic factor. Three
transcobalamins carry it to the tissues.
In most cases, the disease is due to insufficient
intrinsic factor.
Homocysteine is high in pernicious anemia, and
may be responsible for the symptoms.
Synthesis requires more than 20 genes.

Biosynthesis of adenosylcobalamin

Adenosylcobalamin reversibly forms an adenosyl free radical

About 12 different adenosycobalamin-dependent enzymes are known. In mammals,

there are two reactions that use cobalamin; methylmalonyl~CoA mutase and
methionine synthase.
methylmalonyl~CoA mutase. This enzyme converts methylmalonyl~CoA to
succinyl~CoA, an essential step in the metabolism of odd-chain fatty acids.

Carbon skeleton rearrangement in the methylmalonyl-CoA mutase reaction

Defect in this enzyme-> methylmalonic aciduria, often fatal in infancy due to low blood pH.
treatment is diet restricted in odd-chain fatty acids and low in Ile, Leu, and Met.

Bacterial methylmalonyl~CoA mutase

View of the active site:

Notes: deoxyadenosine
not seen (disordered)
DMB is swung away and
His 610 is liganded to Co.

2-carboxypropyl~CoA-magenta
adenosylcobalamin-green

Proposed mechanism of the methylmalonyl~CoA mutase reaction

1. Homolytic cleavage generates

free radical.
2. Abstraction of hydrogen atom
generating substrate radical
3. C skeleton rearrangement as
product radical is formed
4. Product radical abstracts hydrogen
atom from 5-deoxyadenosine.
5. Release of product and
reformation of coenzyme.

Succinyl~CoA cannot be directly consumed by the Citric Acid Cycle

Succinyl~CoA---> succinate--->fumarate----malate
to cytosol

malate
NADP+
NADPH + H+

malic enzyme
(malate dehydrogenase, decarboxylating)

pyruvate + CO2

Ketone bodies: Metabolic fuel under conditions of carbohydrate deficiency

Fat burns in the flame of carbohydrates
In mammals, there is no pathway for the formation of glucose from acetyl~CoA. Acetyl~CoA
can be oxidized via the citric acid cycle as long as sufficient OAA is present.
Between meals or during fasting, gluconeogenesis in the liver produces glucose for the perpheral
tissues. This diverts OAA from the citric acid cycle, and eventually the cycle cannot turn.
The liver then synthesizes ketone bodies which essentally serve as the water-soluble equivalent
of acetyl~CoA.
The skeletal muscle, heart muscle, kidney, and brain switch from using glucose as the main energy
source to using ketone bodies during prolonged fasting. Heart muscle and renal cortex
use acetoacetate in preference to glucose.
Abnormally high levels of ketone bodies are found in the blood of untreated diabetics.

Ketogenesis: reaction forming acetoacetate from acetyl~CoA

Notes:
Occurs in liver mitochondria
1. A reversal of the final step of
-oxidation.
2. Similar to reverse of thiolase. An
enzyme acyl-thioester intermediate.
3. Lyase reaction ia analogous to
reverse of citrate synthase reaction.
acetoacetate may be further reduced
to D--hydroxybutyrate by -hydroxy
butyrate dehydrogenase.

Metabolic conversion of ketone bodies to acetyl~CoA

Notes:
Occurs in perpheral tissues. Liver lacks the
3-ketoacyl-CoA transferase, and thus does not
use the ketone bodies it produces.

Comparison of fatty acid -oxidation and fatty acid biosynthesis

The formation of malonyl~CoA is the committed step in fatty acid synthesis

Irreversible reaction catalyzed by acetyl CoA carboxylase (ACC):
acetyl~CoA + ATP + HCO3-

malonyl~CoA + ADP + Pi + H+

ACC contains a biotin prosthetic group, and the reaction mechanism is similar to
pyruvate carboxylase and propionyl~CoA carboxylase reactions.
The two steps in the reaction:
Biotin----Enzyme + ATP + HCO3CO2-Biotin----Enzyme + acetyl~CoA

<===> CO2-Biotin----Enzyme + ADP + Pi

malonyl~CoA + Biotin----Enzyme

Notes: In E. coli, 3 subunits: biotin carboxylase, transcarboxylase, biotin-carboxyl carrier protein.

In birds and mammals a single polypeptide chain has all three functions.
ACC is subject to hormonal regulation. Dephosphorylated form is active, phosphorylated form is
less active. Glucagon and epinephrine stimulate phosphorylation, Insulin stimulates dephosphorylation.
Citrate activates and palmitoyl~CoA inhibits the enzyme
Phosphorylation leads to depolymerization.

Mammalian Fatty Acid Synthase (FAS)

ketoacyl-ACP synthase

malonyl/acetyl-CoA
ACP transacylase

enoyl-ACP reductase

palmitoyl thioesterase

ketoacyl-ACP reductase
hydroxyacyl-ACP dehydratase

Mammalian enzyme is a homodimer of 272 kDa subunits

Member of the megasynthase family.
In E. coli 7 different enzymes + ACP

The phosphopantetheine prosthetic group of ACP is derived from CoA

In E. coli, ACP is a separate 125-amino acid protein, in mammals it is part of FAS

Reaction cycle for the biosynthesis of fatty acids by FAS

Notes:
1. (a) MAT puts acetyl unit on ACP
1. (b) acetyl unit transfered to KS site
2. MAT puts malonyl unit on ACP
3. KS condenses yeilding acyl-ACP
4. KR, DH, ER act on the acyl-ACP
5. acyl-ACP transferred to KS site
back to step 2
after 7 cycles get palmitoyl-ACP
TE catalyzes hydrolysis, yeilding palmitate

Mechanism of carbon-carbon bond formation in fatty acid biosynthesis

Notes:
The CO2 that was added in the ACC reaction
is lost as CO2 and does not appear in the fatty acid.

Loss of CO2 results in resonance-stabilized carbanion

A molecule of palmitate costs ~136 ATP

8 acetyl~CoA + 14 NADPH + 6 H+ + 7 ATP
8 acetyl~CoA
14 NADPH
7 ATP
Total

palmitate + 14 NADP+ + 8 CoA + 6 H2O + 7 ADP

@ 10 ATP/acetyl~CoA
@ 3.5 ATP/NADPH

80 ATP
49 ATP
7 ATP
136 ATP

Citrate carries acetyl groups from the mitochondrion to the cytosol for
fatty acid synthesis
Acetyl~CoA is generated in the mitochondrion
by pyruvate dehydrogenase. Excess acetyl~CoA
is shipped to the cytosol for storage as fat.
Citrate is passed to the ctytosol.
ATP-citrate lyase regenerates the acetyl~CoA
and OAA in cytosol.
Malic enzyme produces the NADPH that may be
used in fatty acid synthesis.

tricarboxylate transport system for transfer of

acetyl CoA from mitochondrion to cytosol

The elongation and desaturation of fatty acids are accomplished

by additional enzyme systems

Elongases are present on the cytosolic face of the ER and in the mitochondrion.
Desaturases are mainly in the ER membrane.
Mammals cannot introduce double bonds beyond C9, thus linoleic and linolenic acids are
essential fatty acids.

Synthesis of triacylglycerols
ER, peroxisomes

ER, mitochondrion

In ER membrane, these 2 form a complex

Regulation of Fatty Acid Metabolism

Fatty acid metabolism is coordinated
with other aspects of metabolism.
Hormonally regulated by pancreatic
a and b cells, which sense metabolic
status and secrete glucagon and insulin,
respectively.
The simultaneous synthesis and oxidation
of fatty acids in liver cells is prevented.
Malonyl~CoA inhibits carnitine palmitoyl
transferase I.
Long term regulation-synthesis of ACC
adipose lippoprotein lipase, and FAS
stimulated by insulin, inhibited by
glucagon, epinephrine.
A diet high in polyunsaturated FA also
causes decreased FAS, ACC.

The Biosynthesis of membrane lipids and steroids

Phospholipids and Glycolipids may have a glycerol or sphingosine skeleton

Glycerophospholipid synthesis starts with phosphatidic acid or diacylglycerol

The synthesis of phospholipids requires an activated intermediate

For the glycerophospholipids, a diaclyglyceride is combined with an alcohol. Either
species may be activated, depending on the source of the reactants.

Examples where the alcohol is activated:

Phosphatidylethanolamine
Phosphatidylcholine
Examples where the diacylglyceride is activated:
phosphatidylglycerol
phosphatidylinositol

Activation of the alcohol by phosphorylation and cytidylylation

phosphorylation of alcohol

addition of CMP

Notes: Liver can also convert phosphatidylethanolamine

to phosphatidylcholine by adding 3 methyl groups
with S-adenosylmethionine as the methyl donor.

Figure 25-78 The biosynthesis of phosphatidylethanolamine

Page 970

and phosphatidylcholine.

Phosphatidylserine is formed from phosphatidylethanolamine by

an exchange of the polar head group

Figure 25-79 Phosphatidylserine synthesis.

Page 971

Activation of the diacylglyceride in the formation of phosphatidylinositol

and phosphatidylglycerol

Figure 25-80 The biosynthesis of phosphatidylinositol and phosphatidylglycerol.

Page 972

Cardiolipin is synthesized from two molecules of phosphatidylglycerol

Glycerol ether phospholipids contain an ether linkage at the glycerol C1

Plasmologens-hydrocarbon linked to C1 by a vinyl ether linkage

-O-CH=CH-R
Alkylacylglycerophospholipids-alkyl substituent attached to C1 by ether linkage

-O-R

Plasmologens and other ether phospholipids are synthesized from DHAP

1. Exchange of acyl group for

an alcohol.
2. Reduction of ketone to alcohol.
3. acylation at C2 of glycerol.
4. dephosphorylation at glycerol C3.
5. reaction with CDP-ethanolamine.
6. Desaturase in ER introduces
double bond.

Figure 25-82 The biosynthesis of ethanolamine plasmalogen via a

pathway in which 1-alkyl-2-acyl-sn-glycerolphosphoethanolamine
is an intermediate.
Page 973

Platelet-activating factor is an ether phospholipid signalling molecule

(CH2)15-CH3
CH3

+
(CH3)3

Platelet-activating factor
Platelet-activating factor is a soluble signalling molecule that acts on cells containing a specific
7TM receptor. The presence of an acetyl group at the glycerol C2 instead of a long chain acyl
group makes it somewhat water-soluble. It acts at [10-9-10-10] and perhaps as low as [10-12]M.
Implicated in a number of allergic and inflammatory responses. Aggregation of blood platelets,
smooth muscle contraction, activation of immune cells, reduction in blood pressure, decreased
heart output, stimulation of glycogenolysis. Mediator of anaphylactic shock.

Sphingolipids are synthesized from ceramide

Ceramide comes from Palmitoyl~CoA, serine, and an acyl~CoA

Sphingomyelin is a structural component of nerve cell membranes

Figure 25-83 The synthesis of sphingomyelin from N-acylsphingosine and phosphatidylcholine.

Page 974

Most sphingolipids are sphingoglycolipids

Four main classes:

ceramide head group

Cerebrosides

monosaccharide ()

Sulfatide

monosaccharoside sulfate ()

Globosides

neutral oligosaccharides

Gangliosides

sialic acid-containing oligosaccharides

Synthesis involves activated sugars: UDP-glucose, UDP-galactose, UDP-N-acetylgalactosamine

CMP-NANA, etc.; transferase steps catalyzed by a large array of specific glycosyltransferases.

Main classes of Sphingoglycolipids

Brain lipids
Brain lipids (white matter)

A large number of gangliosides have been identified

Most abundant in nervous system (grey matter, 6%)

The biosynthesis of sulfatides involves PAPS

Figure 25-87 The biosynthesis of sulfatides.

How E. coli makes PAPS

Examples of ganglioside structure

NANA is synthesized from N-acetyl-mannosamine-6-P and PEP

Sphingolipids are broken down in lysosomes, defects in turnover result

in severe diseases

GM2-activator proteinstimulated hydrolysis

of ganglioside GM2 by hexosaminidase A
Notes:
Sphingolipid activator proteins stimulate
sequential removal of carbohydrate units.
Diseases can be screened for.
Diseases of sphingolipid breakdown

Sphingolipid storage diseases

Strategys for dealing with these diseases range from inhibition of the biosynthetic pathways to
gene therapy.
Respiratory distress syndrome-Cant make enough dipalmitoyl phosphatidyl choline, the major lung
surfactant. Frequently observed in premature infants.

Cholesterol is synthesized from acetyl~CoA in three stages

1. Synthesis of isopentenyl pyrophosphate, an activated isoprene unit.
2. Condensation of 6 molecule of IPP to form squalene.
3. Squalene cyclizes and the tetracyclic product is converted to cholesterol.

Cholesterol is a component of membranes and a precursor to steroids and bile salts.

Stage 1: formation of isopentenyl pyrophosphate

Stage 2: the condensation of isoprenoid units

HMG-CoA reductase catalyzes an irreversible reaction

that is the committed step. It is highly regulated.

mechanism of IPP isomerase

Likely mechanism for the prenyl transferase reaction

Page 947

Formation of squalene

Page 946

Figure 25-47 Formation of squalene from isopentenyl pyrophosphate and dimethylallyl pyrophosphate.

The squalene synthetase reaction

carbocation inserts into double bond to

form cyclopropyl compound

loss of pyrophosphate gives primary carbocation,

rearranges to tertiary carbocation, reduced by NADPH

Stage three: Lanosterol is produced by squalene cyclization

Figure 25-42 Squalene. (a) Extended conformation. Each box contains one isoprene unit. (b) Folded
in preparation for cyclization as predicted by Bloch and Woodward.

The cyclization reaction occurs in two steps: Squalene epioxidase forms 2,3 oxidosqualene,
lanosterol synthase brings about cyclization by protonation of the epioxide, the cyclization
involves a series of hydride and methyl shifts.

The squalene epioixidase reaction

The lanosterol synthase reaction

enzyme protonates the epioxide, forming

a cation.

a series of methyl and hydride migrations

probably yeilds carbocation at position C8

elimination of a proton gives C8-C9

double bond

Lanosterol is converted to cholesterol in a 19 reaction sequence

Page 952

Cholesterol is esterified by acyl-CoA:cholesterol acyl transferase ACAT

Lipids are transported in lipoprotein complexes

Figure 12-74

Model for plasma triacylglycerol and cholesterol transport

in humans.

LDL receptor-mediated endocytosis in mammalian cells

Page 953

Long-term feedback regulation of cholesterol and LDL receptor biosynthesis

Page 955

Figure 25-58 Model for the cholesterol-mediated proteolytic activation of SREBP.

HMG-CoA reductase is regulated by reversible phosphorylation

P
AMPK
enzyme

enzyme

?
more active

less active

LDL-receptor activity controls cholesterol homeostasis

Liver removes IDL from serum, therefore the

number of LDL receptors plays a direct role.
high cholesterol diet leads to repression of
LDL receptor synthesis.

Page 956

Strategies for reducing serum cholesterol

1. Low cholesterol diet.
2. increase elimination (ingestion of anion exchange resins).
3. competitive inhibitors of HMG-CoA reductase.

Figure 25-60 Competitive inhibitors of HMG-CoA reductase used for the treatment of
hypercholesterolemia.
Page 957

The steroid hormones are derived from cholesterol

progestins-regulate events during pregnancy
glucocorticoids-promote gluconeogenesis,
reduce inflammation
mineralocorticoids-regulate ion balance via
effects on kidney.
androgens-male sexual development and
characteristics
estrogens-female sexual characterisitics and
development
Act via nuclear receptors that control gene
transcription.
Circulating levels controlled by signals from brain:
hypothalamus--->releasing factor---->
tropin (pituitary)----->steroid synthesis in target
tissue.
Human enzyme deficiencies have been identified.
Figure 25-61 Simplified scheme of steroid biosynthesis.

Page 958

DES-promotes growth of beef cattle, causes cancer.

oral contraceptives, estrogen and progesterone
analogues

Eicosanoid hormones are derived from polyunsaturated fatty acids

Locally acting hormones

present at very low concentration
act through specific receptors
in some cases cAMP or cGMP is elevated
TXA2-causes platelet aggregation.
PGI2-inhibits platelet aggregation, relaxes coronary arteries.
PGE-inhibits gastric secretion
PGF2-stimulates urerine contraction, induces labor.

Arachidonate is the major precursor of eicosanoid hormones

e.g. prostaglandins with 2 double bonds
Leucotrienes, Hepoxilins, Lipoxins
linear pathway, lipoxygenases
PLA2

phospholipids

Arachidonate

diacylglycerols

prostaglandin synthase
Prostaglandin H2 (PGH2)

prostacyclin

other Prostaglandins

Thromboxanes

Stage 1: release of arachidonate

Corticosteroids inhibit phospholipase A2

Aspirin inhibits prostaglandin synthesis by acting on PGH synthase

Humans contain 3 related PGH synthase enzymes (isoforms)

activities: cyclooxygenase (COX), peroxidase

tyrosyl-radical mediated addition of 2 molecules of O2

Aspirin acetylates the enzyme, blocking the substrate channel

Other COX inhibitors

Figure 25-70 Some nonsteroidal anti-inflammatory drugs (NSAIDs).

The COX-2 enzyme is responsible for inflammation

Activated normally by cytokines, protein growth factors, endotoxins
COX-2 has a bigger channel than does COX-1

COX-2 inhibitors