Metabolisme Heme

• Biosintesis Heme dan Porphyrias

• Degradasi Heme : ikterus : Jaundice
 Metabolisme Porfirin
Learning Objectives:

1. Mengerti dan mengenal struktur pofirin

2. Mengerti sintesis dan degradasi porfirin

3. Mengerti pathogenesis porfirin

4. Mengerti degradasi heme dan pembentukan bilirubin

5. Mengerti pembentukan jaundice

 Metabolism porfirin
- Porfirin adalah senyawa cincin yang dibentuk
dari gabungan 4 cincin pirol melalui jembatan metil

- Sifat khas porfirin pembentukan khas dgn ion logam

yg terikat pada aton N cincin pirol (metalo porfirin)

- Protein heme secara cepat disintesis dan didegradasi

6 to 7 g per hari hemoglobin turned over
Struktur Porfirin
- Cincin (4 pirol) dgn jembatan metil

- rantai samping dapat bervariasi

- - uroporphyrin memiliki rantai asetat dan propionat
- - coproporphyrin memiliki rantai metil dan propionate

- urutan rantai menentukan subkelompok porfirin: hanya

Porfirin tipe III biasanya penting bagi manusia
 Biosintesis porfirin

COO-
COO- CH2
CO2
CH2 COO- CH2
CH2 + CH2 C=O + HS-CoA
NH3+ CH2
C=O
S-CoA Glisin NH2
-Amino
Suksinil-KoA
Levulinat = ALA

Tahap 1
Tahap 2: Sintesis dasar unit cincin
COO-
COO- COO- CH2
CH2 CH2 CH2
COO-
CH2 C C
CH2 -2H2O
C=O C CH
CH2 N
CH2 CH2 H
C=O
CH2 NH2 NH2
Porfobilinogen
NH2

the basic building block

Ferrochetalase Iron is added as
M V Fe2+
I C
C N
M H M
Fe 2+H N II
IV N H
P H V
N
C C
III
P M

HEME
 Porfirinogen
- precursors porfirin - chemically reduced
- tidak berwarna
- senyawa antara dlm sintesis heme

Biosintesis Heme
- Terjadi di hati dan sumsum tulang (eritroblas)
• sitokrom p450 dalam hati
• hemoglobin di sumsum tulang
• Produksi heme sama dengan sintesis globin di sumsum
• variabel dalam hati tergantung pada keseimbangan heme pool
Biosintesis Heme ada 2 tahap : sintesis porfirin dan heme
Mitochondria PORPHYRIAS
GLYCINE + SuccinylCoA Agent Orange
ALA synthase
3p21/Xp11.21
-aminolevulinic acid(ALA)
ALA-dehydratase
ALA dehydratase
9q34 Deficiency porphyria
Porphobilinogen(PBG)
Acute intermittent
PBG deaminase porphyria Not
11q23
hydroxymethylbilane photosensitive

Uroporphyrinogen III Congenital erythropoietic

cosynthase 10q26 porphyria
uroporphyrinogen III
Uroporphyrinogen Prophyria
decarboxylase cutanea tarda
1q34
coprophyrinogene III
Coproporphyrinogen Herediatary
oxidase 9 coproporphyria
Protoporphyrinogene IX
Protoporphyrinogen Variegate
protoporphyrin IX oxidase 1q14 porphyria

Ferrochelatase Erythropoietic
Heme 18q21.3 protoporphyria
recessive
 Table 1- The porphyrias. You are responsible for the enzyme defects in red

Type Enzyme Major Symptoms Laboratory tests

Involved
Acute intermittent Uroporphyrinogen Abdominal pain urinary porphobilinogen 
porphyria synthase Neuropsychiatric
Congenital Uroporphyrinogen Photosensitivity urinary uroporphyrin 
erythropoietic cosynthase
porphobilinogen 
porphyria
Porphyria cutanea Decarboxylase Photosensitivity urinary uroporphyrin 
tarda
porphobilinogen 
Variegate porphyria Oxidase Photosensitivity urinary uroporphyrin 
Abdominal pain
fecal coproporphyrin 
Neuropsychiatric
fecal protoporphyrin 
Erythropoietic Ferrochelatase Photosensitivity fecal protoporphyrin 
protoporphyria
red cell protoporphyrin 
 Porphyrias
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
 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
 Acute hepatic porphyrias

- acute intermittent porphyria (hydroxymethylbilane synthase)

- hereditary coproporphyria (coprophyrinogen oxidase)
- variagate porphyria (protoporphyrinogen oxidase)

- similar symptoms - acute attacks of gastrointestinal

pain, neurologic/psychologic, cardiovascular

- often precipitated by drugs, particularly barbituates,

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

Treatment for Porphyrias

- medical support for vomiting and pain

- hemin, decreases ALA synthase synthesis
- avoidance of sunlight and precipitating drugs, factors
 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”
 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
 Heme Degradation
Heme Catabolism
HEME
NADPH O2
(opens the porphyrin ring)
Fe+3 NADP+
BILIVERDIN
NADPH

NADP+
BILIRUBIN

BILIRUBIN diglucuronide

BILE
 Degradation of Heme
Heme dari sel darah merah (85%)
sisanya dari pergantian sitokrom, p450, eritrosit
imature

Umur eritrosit 120 hari, terdegradasi oleh sistem

reticuloendothelial (RE) (2)

Pembentukan Bilirubin
Sel RE heme oxygenase microsomal :
- membutuhkan NAPDH, O2
- jembatan metenil hidroksilat
- Fe 2+ teroksidasi menjadi Fe 3 +
- Reaksi kedua memotong cincin
- CO dirilis dengan Fe 3 +

menghasilkan biliverdin pigmen hijau

direduksi menjadi bilirubin (merah-jingga): pigmen empedu
 Pengambilan bilirubin oleh liver
hidrofobik - diangkut oleh albumin 
mengikat protein intraseluler (ligandin)di hati

beberapa obat anionik dapat menggantikan

bilirubin, kerusakan SSP pada bayi (salisilat)

Pembentukan bilirubin diglukuronat

Konjugasi dgn 2 mol glukuronat:
- meningkatkan daya larut (solubility)
- bilirubin glukuroniltransferase
- UDP- asam glukuronat sbg donor
- conjugasi dgn albumin ikatan lemah

ekskresi bilirubin menjadi empedu

-- bilirubin tak terkonjugasi tidak diekskresikan
BLOOD
Stercobilin
CELLS Urobilin
excreted in feces
Hemoglobin excreted in urine

Globin
Urobilinogen
Heme
O2 formed by bacteria KIDNEY
reabsorbed
Heme oxygenase INTESTINE into blood
CO

Biliverdin IX via bile duct to intestines

NADPH
Biliverdin Bilirubin diglucuronide
reductase (water-soluble)

NADP+ 2 UDP-glucuronic acid

Bilirubin Bilirubin
(water-insoluble) LIVER
(water-insoluble) via blood
to the liver

Catabolism of hemoglobin
 Jaundice
Hyperbilirubinemia:
Two forms:
Direct bilirubin: Conjugated with
glucoronic acid
Indirect bilirubin: unconjugated,
insoluble in water.
 Jaundice (icterus)

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

- not a disease, but symptom of underlying disorders

penyakit kuning hemolitik
- hati dapat menangani 3000 mg bilirubin / hari - normal adalah 300
- hemolisis masif menyebabkan lebih dari yang bisa diproses
- tidak bisa terkonjugasi
- peningkatan bilirubin diekskresikan ke dalam empedu,
- urobilinogen meningkat dalam darah, urin
- bilirubin tak terkonjugasi dalam darah meningkat = ikterus
- Kotoran pucat dan berwarna tanah liat
Ikterus Hepatoseluler

- kerusakan hati (sirosis atau hepatitis) menyebabkan peningkatan

kadar bilirubin dalam darah karena konjugasi menurun
- bilirubin terkonjugasi tidak efisien diekspor ke empedu
jadi berdifusi ke sirkulasi darah
- peningkatan urobilinogen dalam sirkulasi enterohepatik jadi air
seni lebih gelap dan tinja berwarna pucat, berwarna tanah liat
- Kadar AST dan ALT meningkat
- mual dan anoreksia
Penentuan kadar bilirubin
 Figure 3. Examples of hyperbilirubinemia

A. Hemolytic anemia B. Hepatitis C. Biliary duct stone

excess
hemolysis

Urobilinogen Urina
Urobilinogen feses
Bilirubin Urina + +
 unconjugated bilirubin
 unconjugated bilirubin  unconjugated bilirubin
(in blood)
(in blood)
 conjugated bilirubin (in blood)
 conjugated bilirubin  conjugated bilirubin
(released to bile duct)
(in blood) (in blood)
 Table 2- Genetic Disorders of Bilirubin Metabolism

Condition Defect Bilirubin Clinical Findings

Crigler-Najjar severely defective Unconjugated Profound jaundice
syndrome UDP-glucuronyltransferase bilirubin 
Gilberts reduced activity of Unconjugated Very mild jaundice
syndrome UDP-glucuronyltransferase bilirubin  during illnesses
Dubin- abnormal transport of Conjugated Moderate jaundice
Johnson conjugated bilirubin into bilirubin 
syndrome the biliary system
 The Madness of Inbreeding

George III : Severe abdominal pain, mental confusion, dark urine.