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Lippincott's
Illustrated Reviews:
Biochemistry

Chapter 21

Conversion of Amino Acids to

Specialized Products

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Iron in an organism:
total 3-4 g (2,5 g in hemoglobin)
heme, ferritin, transferrin
two oxidation states: Fe2+, Fe3+
Function:
1. Heme iron:
hemoglobin, myoglobin, cytochrom-c oxidase, catalase
2. Non-heme iron:
Fe-S complexes (xanthine oxidase), DNA synthesis (ribonucleotide reductase)

Free iron is toxic !

Regulation:
at the level of absorption

Iron-containing proteins:
1. Heme proteins
Hemoglobin
Myoglobin
Enzymes that contain heme as their prosthetic group (catalase, peroxidase,
NO synthase)

2. Nonheme proteins
Transferrin
Ferritin
Enzymes that contain iron at the active site
Iron-sulphur proteins

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Iron metabolism:
Recommended dietary allowance 10-15 mg
10-50 mg in the diet (only 10-15% is normally absorbed)

Iron distribution:
g

Hemoglobin

2,5

68

Myoglobin

0,15

Transferrin

0,003

0,1

Ferritin, tissue

1,0

27

Ferritin, serum

0,0001

0,004

Enzymes

0,02

0,6

Total

3,7

100

Structure of Heme

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PORPHYRIN METABOLISM
Figure 21.2

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ALA synthase

Mitochondrial location
Rate limiting
Pyridoxal phosphate
Regulation of enzyme levels
by iron and protohem
Porphobilinogen
Synthase
ALA dehydratase

Heme synthesis
Sources for synthesis
1. Glycin and citric acid cycle intermediates
2. Forming aminolevulinic acid-cosubstrate pyridoxal phosphate, tare
limiting step
3. HEME (Iron (II))
4. HEMIN (Iron (III))
5. EXTRA HEME CONVERTED TO HEMIN
6. Hemin decreases activity of ALAS1
DRUGS METABOLISED BY HEME ENZYME WILL INCREASE ALAS 1 activity

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Regulation of ALA Synthase

Level of enzyme synthesis
Enzyme synthesis, as well as its transport to the mitochondria, is
inhibited by elevated levels of heme and hemin, the Fe3+ oxidation
product of heme.
Enzyme synthesis is upregulated by a large number of drugs
including barbiturates, steroids with a 4,5 double bond (e.g.
testosterone) and some oral contraceptives: These drugs are
metabolized by the microsomal cytochrome P450 monooxygenase system, a heme-containing protein.
Level of enzyme activity
Heme and hemin inhibit ALA synthase activity which requires
pyridoxal phosphate (Vitamin B6) as a coenzyme

PORPHYRIN METABOLISM

Figure 21.4

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PORPHYRIN METABOLISM
Figure 21.5

3.Porphyrias
Disease

Enzyme

Organ Pathology

Acute Intermittent
Porphyria

Uroporphyrinogen I synthase
Neuropsychiatric
deficiency
Abdominal pain
(porphobilinogen deaminase
or hydroxymethylbilane synthase)

Congenital Erythropoietic
Porphyria

Uroporphyrinogen III
cosynthase deficiency

Porphyria Cutanea Tarda

Uroporphyrinogen decarboxylase Skin

Hereditary Coproporphyria

Coproporphyrinogen oxidase

Skin, Abdominal pain,

Neuropsychiatric

Variegate Porphyria

Protoporphyrinogen oxidase

Skin, Abdominal pain,

Neuropsychiatric

Protoporphyria

Ferrochelatase

Skin, Abdominal pain,

Neuropsychiatric

Lead poisoning

Inhibition of ALA dehydratase

and ferrochelatase

Nervous system,
blood etc.

Skin

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PORPHYRIN METABOLISM
(continued)
Figure 21.6

Skin eruptions in a patient with porphyria

cutanea tarda.

PORPHYRIN METABOLISM
(continued)
Figure 21.7

Urine from a patient with porphyria cutanea

tarda (right) and from a patient with normal
porphyrin excretion (left).

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FATE OF RED BLOOD CELLS

Life span in blood stream is 60-120 days

RBCs are phagocytosed and/or lysed

Normally, lysis occurs extravascularly in the
reticuloendothelial system subsequent to RBC
phagocytosis
Lysis can also occur intravascularly (in blood stream)

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Extravascular Pathway for RBC Destruction

(Liver, Bone marrow,
& Spleen)
Phagocytosis & Lysis

Hemoglobin

Globin

Heme

Amino acids

Fe2+

Amino acid pool

Bilirubin

Excreted

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PORPHYRIN METABOLISM
Figure 21.9

Formation of bilirubin from heme

and its conversion to bilirubin
diglucuronide.
UDP = uridine diphosphate;
CO = carbon monoxide; NADP(H)
= nicotinamide adenine dinucleotide
phosphate.

DEGRADATION OF HEME TO BILIRUBIN

85% is derived from RBCs

P450 cytochrome

In normal adults this results in

a daily load of 250-300 mg of
bilirubin
Normal plasma concentrations
are less then 1 mg/dL
Hydrophobic transported by
albumin to the liver for further
metabolism prior to its excretion

unconjugated bilirubin

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PORPHYRIN METABOLISM
Figure 21.9

Formation of bilirubin from heme

and its conversion to bilirubin
diglucuronide.
UDP = uridine diphosphate;
CO = carbon monoxide; NADP(H)
= nicotinamide adenine dinucleotide
phosphate.

NORMAL BILIRUBIN
METABOLISM

Uptake of bilirubin by the liver is mediated by a carrier

protein (receptor) (lack of :Dubin-Johnson syndrome)
Uptake may be competitively inhibited by other
organic anions
On the smooth ER, bilirubin is conjugated with
glucoronic acid, xylose, or ribose
Glucoronic acid is the major conjugate - catalyzed by
UDP glucuronyl tranferase

Conjugated bilirubin is water soluble and is secreted

by the hepatocytes into the biliary canaliculi
Converted to stercobilinogen (urobilinogen)
(colorless) by bacteria in the gut
Oxidized to stercobilin which is colored
Excreted in feces
Some stercobilin may be re-adsorbed by the gut and
re-excreted by either the liver or kidney

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PORPHYRIN METABOLISM

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HYPERBILIRUBINEMIA
Increased plasma concentrations of bilirubin (> 3 mg/dL) occurs when
there is an imbalance between its production and excretion
Recognized clinically as jaundice

Types of Jaundice (Icterus)

1. Prehepatic jaundice (hemolytic jaundice)
a. acute hemolytic anemia
b. neonatal physiologic jaundice
c. chronic hemolytic anemia
2. Hepatic jaundice
a. conjugation failure: neonatal physiologic jaundice, CriglerNajjar disease, Gilbert's syndrome,
b. bilirubin transport disturbances: Dubin-Johnson disease
c. diffuse hepatocellular damage or necrosis
d. intrahepatic obstruction
3. Post-hepatic jaundice -obstructive
Obstruction of the common bile duct by stones, neoplasms or
spasms.

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PORPHYRIN METABOLISM
Figure 21.11

Jaundiced patient, with the sclerae of his eyes

appearing yellow.

PORPHYRIN METABOLISM
Figure 21.12
Alterations in the metabolism of heme. A.
Hemolytic jaundice.
B. Neonatal jaundice. squared CB =
conjugated bilirubin; circled B = bilirubin;
squared U = urobilinogen; triangled S =
stercobilin; UDP = uridine diphosphate.

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Prehepatic (hemolytic) jaundice

Results from excess production of

bilirubin (beyond the livers ability to
conjugate it) following hemolysis

Excess RBC lysis is commonly the

result of autoimmune disease;
structurally abnormal RBCs (Sickle
cell disease);pyruvate kinase
deficienciy

High plasma concentrations of

unconjugated bilirubin (normal
concentration ~0.5 mg/dL)

Intrahepatic jaundice
Impaired uptake, conjugation,
or secretion of bilirubin
Reflects a generalized liver
(hepatocyte) dysfunction
In this case,
hyperbilirubinemia is usually
accompanied by other
abnormalities in biochemical
markers of liver function

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Posthepatic (obstructive ) jaundice

Caused by an obstruction of the

biliary tree

Plasma bilirubin is conjugated, and

other biliary metabolites, such as
bile acids accumulate in the plasma

Characterized by pale colored stools

(absence of fecal bilirubin or
urobilin), and dark urine (increased
conjugated bilirubin)

In a complete obstruction, urobilin

is absent from the urine

Diagnoses of Jaundice

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Neonatal Jaundice

Common, particularly in premature infants

Transient (resolves in the first 10 days)

Due to immaturity of the enzymes involved in bilirubin conjugation

High levels of unconjugated bilirubin are toxic to the newborn due to its
hydrophobicity it can cross the blood-brain barrier and cause a type of mental
retardation known as kernicterus

If bilirubin levels are judged to be too high, then phototherapy with UV light is
used to convert it to a water soluble, non-toxic form

If necessary, exchange blood transfusion is used to remove excess bilirubin

Phenobarbital is oftentimes administered to mother prior to an induced

labor of a premature infant crosses the placenta and induces the synthesis
of UDP glucuronyl transferase

Jaundice within the first 24 hrs of life or which takes longer then 10 days to
resolve is usually pathological and needs to be further investigated

PORPHYRIN METABOLISM
Figure 21.13

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Causes of Hyperbilirubinemia

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Gilberts Syndrome-hepatic jaundice

Benign liver disorder
of the affected individuals inherited it
Characterized by mild, fluctuating increases in unconjugated bilirubin caused
by decreased ability of the liver to conjugate bilirubin often correlated with
fasting or illness

Males more frequently affected then females

Onset of symptoms in teens, early 20s or 30s
Can be treated with small doses of phenobarbital to stimulate UDP
glucuronyl transferase activity

Crigler-Najjar Syndrome
Autosomal recessive
Extremely rare < 200 cases worldwide gene frequency is < 1:1000
High incidence in the plain people of Pennsylvania (Amish and
Mennonites)
Characterized by a complete absence or marked reduction in bilirubin
conjugation
Present with a severe unconjugated hyperbilirubinemia that usually presents
at birth
Afflicted individuals are at a high risk for kernicterus
Condition is fatal when the enzyme is completely absent
Treated by phototherapy (10-12 hrs/day) and liver transplant by age 5

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Dubin-Johnson and Rotors Syndromes

Characterized by impaired biliary secretion of
conjugated bilirubin
Present with a conjugated hyperbilirubinemia
that is usually mild

Iron metabolism:

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Intestinal absorption of iron:

- in the duodenum

- regulation (by the synthesis of apoferritin within mucosal cells)

1. The heme iron (unknown mechanism)
2. The nonheme iron

is not readily absorbed (chelates with oxalates, phytates, etc.)

vit. C increases the uptake

Iron sources:
meat, liver, fish, eggs, green vegetables, cereals

Iron loss:
- daily loss ~ 1-2 mg (cell desquamation, menstruation, pregnancy, multiple
births, lactation)
- bleeding

Recyclation of iron:
- from aged erythrocytes (~ 20 mg)
- transferrin receptors on cells

Iron transport:
Transferrin (Fe3+)

Transferrin + Fe3+ + CO32-

Transferrin 2(Fe3+CO32-)

- only one third saturated with iron

- unsaturated transferrin protects againsts infections (iron overload and infection)
Lactoferrin
- binds iron in milk
- antimicrobial effect (protects newborns from gastrointestinal
infections)
Haptoglobin
- binds hemoglobin in the plasma
Iron storage:
Ferritin (Fe3+)
- storage of iron (hepatocytes, RES, muscles)
- in the blood sensitive indicator of the amount of iron in the body
Hemosiderin
- when iron is in excess (amorphous iron deposition)

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Regulation of iron metabolism:

Hepcidin (a key regulator in iron metabolism)

resorption of iron in the intestine concentration of iron in plasm
mechanism: binding to ferroportin (the iron is trapped in the cell)
increased concentration in inflammation (chronic disease anemia)
reduced production hereditary hemochromatosis

Iron deficiency (sideropenia):

Causes
inadequate intake, reduced resorption, increased loss

Symptoms
reduction of iron stores in liver and bone marrow
decrease in the amount of plasma ferritin
decrease in the percentage saturation of serum transferrin
decrease in the level of Hg, morphological changes of
erythrocytes
microcytic hypochromic anemia (excessive menstrual flow, multiple births,
GIT bleeding)

Therapy
supplementation

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Iron overload hemochromatosis:

Causes
genetic - iron uptake regulation (hereditary hemochromatosis)
treatment of patients with hemolytic anemias
excessive ethanol and iron ingestion
Symptoms
accumulation of iron in the liver, pancreas and heart

Therapy

bloodletting, chelating agents

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