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Majority of amino acids used for de novo protein


synthesis (80%) derives from the degradation of
existing proteins

Only 30 g (6%) used for synthesis of specialized


products

Only 70 g (14%) of total amino acid utilization


is used for energy or stored as glycogen/fatty
acids in the well-fed state (nitrogen balance)

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Porphyrin metabolism
- cyclic compounds that bind metals
- usually iron
- Fe+2 = ferrous
- Fe+3 = ferric
- most common porphyrin in humans is
heme
- one ferrous goup in tetrapyrole ring
- prosthetic group for:
hemoglobin
myoglobin
cytochromes
catalase
tryptophan pyrrolase
- heme proteins are rapidly synthesized
and degraded
- 6 to 7 g per day hemoglobin turned over 3
Structure of Porphyrins
- cyclic, with 4 pyrrole rings attached by methenyl bridges
- side chains may vary
- uroporphyrin has acetate and propionate chains
- coproporphyrin has methyl and propionate chains
- order of chains define subgroups of porphyrins: only
Type III porphyrins are normally important for humans
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Porphyrinogens:
- porphyrin precursors - chemically reduced
- colorless
- intermediate in heme synthesis

Biosynthesis of Heme
- major sites of synthesis: liver and bone marrow
(erythroblasts)
- cytochrome p450 in liver
- hemoglobin in bone marrow
- heme production equal to globin synthesis in marrow
- variable in liver dependent on heme pool balance

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Biosynthesis of Heme
- first and last 3 reactions take place in
mitochondria - all others in cytoplasm
- red blood cells have no mitochondria
so cant make heme
- formation of -aminolevulinic acid (ALA)
- all carbons from glycine and succinyl CoA
- catalyzed by ALA synthase
- requires pyridoxal phosphate
- rate controlling step
- hemin formed from oxidation of heme
- hemin inhibits ALA synthase synthesis

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Biosynthesis of Heme

Formation of porphobilinogen

- dehydration of 2 ALA molecules


- by -aminolevulinic acid dehydrase
- cytoplasmic
- very sensitive to lead and other
heavy metals

- accounts, in part, for lead poisoning


- increased ALA, anemia

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Biosynthesis of Heme
- four porphobilinogens condensed to form
uroporphyrinogen III
- 2 cytoplasmic enzymes:
hydroxymethylbilane synthase
uroporphyrinogen III synthase
- uroporphyrinogen III converted to
coproporphyrinonogen III
- transported back into mitochondria
- converted to protoporphyrinogen IX, then
to protoporphyrin IX
- heme is formed by incorporation of iron (Fe+2)
- partly spontaneous
- ferrochelatase enhances rate
- also inhibited by lead 9
Pathway of Heme Biosynthesis

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Pathway of Heme Biosynthesis

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Pathway of Heme Biosynthesis

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Pathway of Heme Biosynthesis

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Pathway of Heme Biosynthesis

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Pathway of Heme Biosynthesis

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Pathway of Heme Biosynthesis

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HEME SYNTHESIS
Formation of heme involves incorporation
of ferrous iron into protoporphyrin
enzyme:ferrochelatase(heme synthase)
location:mitochondria

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HEME SYNTHESIS
Heme synthesis occurs in most
mammalian cells except mature
erythrocytes (no mitochondria).
85% of heme synthesis occurs in
erythroid precursor cells in bone
marrow, the rest in hepatocytes.

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Regulation of heme
synthesis
ALA synthase 1 (ALAS1) is the key
regulatory enzyme in hepatic
biosynthesis of heme
-ALAS1HEPATC
-ALAS2ERYTHROD
Regulation of heme
synthesis
Heme, through an aporepressor
molecule, acts as a negative
regulator of ALAS1
Heme affects translation of ALAS1
and its transfer from cytosol to
mitochondrion.
Regulation of heme
synthesis
Drugs (barbiturates,griseofulvin) that
are metabolized in the liver by using
cytocrome p450,decrease
intracellular heme concentration
derepress (induce) ALAS1 heme
synthesis increases.
Glucose loading can repress ALAS1
in liver.
PORPHYRIA
Caused by hereditary or acquired defects in heme synthesis
- accumulation and increased excretion of metabolic
precursors (each unique)
- all porphyrias are autosomal dominant,
except congenital erythropoietic porphyria, which is
recessive

Can be hepatic or erythropoietic


- hepatic can be acute or chronic

Those with tetrapyrrole intermediates show photosensitivity


- formation of superoxide radicals
- skin blisters, itches (pruritis)
- skin may darken, grow hair
- hypertrichosis
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Porphyria Cutanea Tarda

- a chronic porphyria
- liver and erythroid tissues
- deficiencey in uroporphyrinogen decarboxylase
- often no symptoms until 4th or 5th decade

Clinical expression determined by many factors:


- hepatic iron overload
- exposure to sunlight
- hepatitis B or C
- HIV
Symptoms include:
- cutaneous rashes, blisters
- urine that is red to brown in natural light, or
pink to red in UV light
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Acute Hepatic Porphyrias

- acute intermittent porphyria (hydroxymethylbilane synthase)


- hereditary coproporphyria (coproporphyrinogen oxidase)
- variagate porphyria (protoporphyrinogen oxidase)
- similar symptoms - acute attacks of gastrointestinal
pain, neurologic/psychologic, cardiovascular

- often precipitated by drugs, particularly barbiturates,


infection, starvation, alcohol
- activators of p450 system - uses up heme,
increases ALA synthase, increases pathologic
metabolites

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Erythropoietic Porphyrias

- congenital erythropoietic porphyria (uroporphyrinogen III


synthase)

- erythropoietic protoporphyria (ferrochelatase)

Symptoms include:
- skin rashes and blisters early in childhood
- cholestatic liver cirrhosis and progressive liver failure

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Treatment for Porphyrias

- medical support for vomiting and pain


- hemin, decreases ALA synthase
synthesis
- avoidance of sunlight and precipitating
drugs, factors

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Acquired Porphyrias
- hexochlorobenzene used as a fungicide in Turkey in 1950s
- thousands of children ate bread from treated wheat

- they acquired porphyria cutanea tarda


due to inhibition of uroporphyrinogen
decarboxylase

-due to hypertrichosis - referred to


locally as the monkey children

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Acquired Porphyrias

Lead poisoning
- inhibition of ferrochelatase, ALA dehydratase
- displaces Zn+2 at enzyme active site
Children
- developmental defects
- drop in IQ
- hyperactivity
- insomnia
- many other health problems

Adults
- severe abdominal pain
- mental confusion
- many other symptoms
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Degradation of Heme
Most heme from RBCs (85%) - rest from
turnover of cytochromes, p450s, immature
erythrocytes
RBCs last 120 days, degraded by
reticuloendothelial (RE) system
Formation of Bilirubin
RE cells microsomal heme oxygenase
- requires NAPDH, O2
- hydroxylates methenyl bridge
- Fe+2 oxidized to Fe+3
- second reaction cleaves ring
- CO released with Fe+3
produces green pigment biliverdin
reduced to bilirubin (red-orange): bile pigments
- explains bruises 33
Degradation of Heme
Uptake of bilirubin by liver
hydrophobic - transported by albumin
- some anionic drugs can displace
bilirubin, CNS damage in infants
(salicylates)
binds intracellular proteins in liver
- ligandin
Formation of bilirubin diglucuronide
conjugation to 2 molecules of glucuronate
- increases solubility
- bilirubin glucuronyltransferase
- UDP-glucuronic acid is the donor
- conjugates also bind albumin, but
much weaker
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Degradation of Heme

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Degradation of Heme

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Degradation of Heme

Excretion of bilirubin into bile


actively transported into bile
- requires energy - susceptible to liver
disease
- unconjugated bilirubin not excreted

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FORMATION OF UROBILIN
IN THE INTESTINE
- bilirubin diglucuronide hydrolyzed and
reduced by bacteria to urobilinogen
- urobilinogen oxidized by bacteria to stercobilin
- brown color of feces
- some urobilinogen is reabsorbed into blood

- enterohepatic urobilinogen cycle (taken to liver


and re-excreted into bile)
- urobilinogen to kidney
- converted to yellow urobilin
- this gives urine its characteristic color
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Jaundice (icterus)

Hyperbilirubinemia
- causes yellow color of skin, nail beds and sclerae

- not a disease, but symptom of underlying disorders

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Types of Jaundice
Hemolytic jaundice
- liver can handle 3000 mg bilirubin/day - normal is 300
- massive hemolysis causes more than can be processed
- cant be conjugated
- increased bilirubin excreted into bile, urobilinogen
is increased in blood, urine
- unconjugated bilirubin in blood increases = jaundice
Obstructive jaundice
- obstruction of the bile duct
- tumor or bile stones
- gastrointestinal pain - nausea
- pale, clay-colored stools
- increased conjugated bilirubin
- can lead to liver damage and increased
unconjugated bilirubin 42
Types of Jaundice

Hepatocellular Jaundice
- liver damage (cirrhosis or hepatitis) cause increased
bilirubin levels in blood due to decreased conjugation
- conjugated bilirubin not efficiently exported to bile
so diffuses into blood
- increased urobilinogen in enterohepatic circulation
- so urine is darker and stool is pale, clay-colored
- AST and ALT levels are elevated
- nausea and anorexia

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Jaundice in Newborns

Premature babies often accumulate bilirubin due to


late onset of expression of bilirubin glucuronyltransferase
- maximum expression (adult level) at ~ 4 weeks
- excess bilirubin can cause toxic encephalopathy
(kernicterus)
- treated with blue fluorescent light
- converts bilirubin to more polar compound
- can be excreted in bile without conjugation
- Crigler - Najjar syndrome is deficiency in bilirubin
glucuronyltransferase

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