METABOLISME PORFIRIN

dan HEME

dr. Pudjadi, SU
dr. Dwi Ngestiningsih, MKes, SpPD

Porfirin

Sifat khas porfirin ialah
pembentukan kompleks dengan
ion logam yang terikat ke atom
nitrogen cincin pirol.

Porfirin besi seperti heme
terdapat pada hemoglobin dan
porfirin ber magnesium
khlorofil, merupakan suatu
pigmen fotosintetik pada
tumbuhan.

Kebanyakan Porfirin alami merupakan struktur porfin dengan rantai samping
yang berbeda-beda.

Metaloporporfirin

1. Porfirin yang mengikat Fe ; Hem

2. Porfirin yang mengikat Mg :Khlorofil

Examples of Some Important Human
and Animal Hemoproteins1

Berbagai hemoprotein Mioglobin Hem + Globin Hemoglobin Sitokhrom a Hem + Protein lain Sitokhrom a3 Sitokhrom b Sitokhrom c Sitokhrom P450 Katalase Peroksidase .

. 3. 2. III. 5. dan IV. γ. Jembatan metenil (-HC=) berlabel α. Cincin pirol Porfin Cincin-cincin berlabel I. dan 8. dan δ. 7. 6. β. 4. Posisi substituen pada cincin terlabel 1. suatu struktur organik siklik yg terbentuk oleh pengikatan 4 cincin pirol melalui jembatan metenil. II. STRUKTUR KIMIA PORFIRIN Struktur inti Porfirin merupakan porfin.

P = propionil Porfin Protoporfirin III / IX 1 = metil 2 = metilen(vinil) 3 = metil 4 = metilen (vinil) 5 = metil 6 = propionil 7 = propionil 8 = metil . A = asetil . STRUKTUR KIMIA PORFIRIN Porfirin merupakan struktur porfin dengan rantai samping Uroporfirin III .

STRUKTUR KIMIA PORFIRIN Porfirin Porfirin merupakan merupakan struktur struktur porfin porfin dengan dengan rantai rantai samping samping .

6P. 4V. 8M. Protoporphyrin III ( IX ) Struktur Protoporfirin III (IX) merupakan struktur Porfin dengan rantai samping : 1M. 2V. 3M. . 5M. 7P.

Struktur kimiawi Protoporfirin IX 1 = metil I II 2 = metilen (vinyl) 3 = metil 4 = metilen vinyl) IV III 5 = metil 6 = propionil 7 = propionil 8 = metil .

Biosintesis Glisin + suksinil-koA Hem ALA  porfobilinogen (pirol) Hidroksi-metil-bilan (tetrapirol linier) Uroporfirinogen III (tetrapirol sirkuler) Coproporfirinogen III Protoporfirinogen III Protoporfirin III Hem .

.Biosintesis porfobilinogen.

.Konversi porfobilinogen menjadi uroporfirinogen Uroporfirinogen sintase I disebut juga porfobilinogen (PBG) deaminase atau hydroksimetilbilan (HMB) sintase.

biosynthesis of the porphyrin derivatives from porphobilinogen Biosintesis derivat porfirin dari porfobilinogen Steps in the biosynthesis of the porphyrin derivatives from porphobilinogen. . Uroporphyrinogen I synthase is also called porphobilinogen deaminase or hydroxymethylbilane synthase.

HEME BIOSYNTHESIS .

.

Pembentukan Hem .

bukan protein • Merupakan porfirin yang mengikat besi • Dibuat dalam mitokhondria & sitoplasma • Bahan pembuat : Glisin dan suksinil- koA • Menurut klasifikasi kimiawi. . porfirin penyusun tubuh kita merupakan protoporfirin III atau protoporfirin IX.Hem • Merupakan zat organik bernitrogen.

hormon estrogen – 5. hematin in vivo • Obat-obatan yang menginduksi ALA sintetase (dimetabolisir di hati dengan menggunakan sitokrom P 450 yang berhem): – 1.Pengendalian biosintesa heme: pada amlev /ALA sintetase . heme – 2. glukosa – 4. apopressor – 3. • Yang menghambat ALA sintetase: – 1. obat-obatan (steroid) – 4. besi dalam bentuk chelated . bahan karsinogen – 3. insektisida – 2.

the principal sites of synthesis are 1. erythroid cells (~85%) 2. hepatocytes (accounting for nearly all the rest of heme synthesis).Regulation of Heme Biosynthesis Although heme is synthesized in virtually all tissues. The differences in these two tissues and their needs for heme result in quite different mechanisms for regulation of heme biosynthesis. .

in particular. which is the committed step in heme synthesis. the P450 class of cytochromes that are important for detoxification. . as a feed-back inhibitor on ALA synthase. Regulation in hepatocytes In hepatocytes. The Fe3+ oxidation product of heme is termed hemin. The rate-limiting step in hepatic heme biosynthesis occurs at the ALA synthase catalyzed step. transport of ALA synthase from the cytosol (its' site of synthesis) into the mitochondria (its' site of action) 3. represses synthesis of the enzyme. 2. heme is required for incorporation into the cytochromes. In addition numerous cytochromes of the oxidative-phosphorylation pathway contain heme. Hemin acts : 1.

ALA synthase. 2. Control has been shown to be exerted on : 1. therefore. Additionally. porphobilinogen deaminase. In reticulocytes (immature erythrocytes) heme stimulates protein (globin) synthesis. Regulation in erythroid cells In erythroid cells all of the heme is synthesized for incorporation into hemoglobin and occurs only upon differentiation when synthesis of hemoglobin proceeds. When red cells mature both heme and hemoglobin synthesis ceases. survive for the life of the erythrocyte (normally this is 120 days). 3. control of heme biosynthesis in erythrocytes occurs at numerous sites. ferrochelatase. . The heme (and hemoglobin) must. the enzyme responsible for iron insertion into protoporphyrin IX.

Katabolisme hem • Terutama hem dari eritrosit .

Dalam sel-sel retikuloendothelial (hepar. Lien & sumsum tulang) Kerusakan eritrosit / hemolisis Terpisahnya hemoglobin Terpisahnya globin dari hem Hem porfirin  biliverdin (hijau) Biliverdin berubah menjadi bilirubin (kuning) yang tidak larut air .

CATABOLISM OF HEME PRODUCES BILIRUBIN The microsomal heme oxygenase system .

Dalam hepar Bilirubin tak larut air glukuronat Bilirubin larut air = diglukuronida bilirubin .

Bilirubin diglucuronide Bilirubin diglukuronida .

METABOLISME BILIRUBIN DI HEPAR .

such as ligandin (a member of the glutathione S-transferase family of enzymes) and Y protein. The process affected in a number of conditions causing jaundice is also shown. langsung . and secretion involved in the transfer of bilirubin from blood to bile Tidak langsung Certain proteins of hepatocytes. conjugation. bind ( langsung) intracellular bilirubin and may prevent its efflux into the blood stream. uptake.

Degradasi bilirubin dalam usus Bilirubin langsung (direk) Bakteri usus Sterkobilinogen (Urobilinogen) Sterkobilin (Urobilin) .

Bilirubin larut air disekresikan ke usus Sel hepar Cairan empedu darah Usus Sebagian berubah  urobilin / sterkobilin Ginjal faeces Urin .

Dalam usus Bilirubin menjadi urobilin / sterkobilin Urobilin mewarnai urin Sterkobilin mewarnai feses .

MRP-2 (multidrug resistancelike protein) atau multispesific oganic anion transporter (MOAT) .

Inherited disorders in bilirubin metabolism lead to hyperbilirubinemia. . 1.Clinical Aspect of Heme Metabolism Clinical problems associated with heme metabolism are of two types. Excess circulation and accumulation of bilirubin (hyperbilirubinemia) results in a yellow-orange discoloration of the tissues and is most easily visible as icteric (yellowish) discoloration in the sclera of the eyes. 2. Disorders that arise from defects in the enzymes of heme biosynthesis are termed the porphyrias that cause elevations in the serum and urine content of intermediates in heme synthesis.

Porphyria • Penyakit genetik • Pada ras kaukasia .

EPP Ferrochelatase Photosensitivity Hepatic Class ALA dehydratase deficiency porphyria. Porphyria Enzyme Defect Primary Symptom Erythropoietic Class Uroporphyrinogen III Congenital erythropoietic porphyria. VP Protoporphyrinogen oxidase Neurovisceral. some photosensitivity Variegate porphyria. ALA dehydratase Neurovisceral ADP Acute intermittent porphyria. PCT Photosensitivity decarboxylase . CEP Photosensitivity cosynthase Erythropoietic protoporphyria. AIP PBG deaminase Neurovisceral Hereditary coproporphyria. HCP Coproporphyrinogen oxidase Neurovisceral. some photosensitivity Uroporphyrinogen Porphyria cutanea tarda.

PORFIRIA ADALAH PENYAKIT GENETIK METABOLISME HEME • Porfiria adalah sekelompok penyakit yang disebabkan oleh abnormalitas jalur biosentesis heme • Fotosensitivitas (lebih senang beraktivitas dimalam hari) dan bentuk tubuh yang aneh (disfigurement) yang diidap oleh sebagian penderita porfiria eritropoietik congenital menimbulkan anggapan bahwa para pasien ini mungkin merupakan suatu prototype werewolf (manusia srigala). Belum ada bukti yang menguatkan anggapan ini. .

. • Jadi. & Pengobatan Porfiria • Dilaporkan ada enam tipe porfiria yang terjadi akibat berkurangnya aktivitas enzim-enzim 3 sampai 8.• Biokimia Mendasari Kausa. pemeriksaan aktivitas satu enzim atau lebih dengan menggunakan sumber yang tepat penting dalam menegakkan diagnosis pasti pada kasus yang dicurigai porfiria. Diagnosis.

. Lisosom yang rusak akan membebaskan enzim-enzim degradatif dan menyebabkan kerusakan kulit dalam derajat yang bervariasi termasuk pembentukan jaringan parut.• Jika kelainan enzim terjadi pada awal jalur reaksi sebelum terjadinya porfirinogen. Radikal oksigen ini merusak lisosom dan organ lain. • Produk-produk oksidasi yaitu turunan porfirin dan padanannya menyebabkan fotosensitifitas yakni suatu reaksi terhadap sinar tampak ( panjang gel 400nm ) •  akan tereksitasi dan kemudian bereaksi dengan molekul oksigen untuk membentuk radikal oksigen. ALA dan PBG akan menumpuk di jaringan dan cairan tubuh secara klinis pasien mengeluh nyeri abdomen dan gejala neuropsikiatrik.

• ALAS1 adalah enzim regulatorik kunci jalur biosintesis heme di hati.griseofulvin) dapat memicu enzim. • pada pasien porfiria. • sebagian besar obat ini melakukannya dengan menginduksi sitokrom P450 yang menggunakan heme sehingga menderepresi (menginduksi) ALAS1.barbiturat.• Konsumsi obat yang dapat memicu sitokrom P450 (yang disebut sebagai penginduksi mikrosom) dapat memicu serangan porfiria. • Obat (mis.peningkatan aktifitas ALAS1 menyebabkan peningkatan kadar berbagai precursor heme  porfiria .

There are 2 forms of ALAS . . = XLSA = congenital sideroblastic anemia = hereditary sideroblastic anemia = hereditary iron-loading anemia = X-linked hypochromic anemia = hereditary hypochromic anemia = hereditary anemia Sideroblasts are erythroblasts with non-heme iron-containing organelles. ALAS2 is an erythroid-specific form of the enzyme and is expressed only in fetal liver and adult bone marrow. whereas the ALAS2 gene is located on the X chromosome. The ALAS1 gene is located on chromosome 3. called siderosomes. Deficiencies in ALAS2 result a disorder called : X-linked sideroblastic anemia. ALAS1 is considered a house-keeping gene and is expressed in all cells.

. or – liver damage with obstruction of the bile duct. The abnormal yellowish pigmentation of the eyes and tissues known as jaundice. the bilirubin and its precursors accumulate in the circulation.Hyperbilirubinemia = Jaundice In individuals with – abnormally high red cell lysis.  hyperbilirubinemia.

Ikterus (kuning) 1. Ikterus neonatorum patologis (Kernicterus) 3. Ikterus neonatorum fisiologis 2. Ikterus pada hepatitis 5. Ikterus karena hemolisis 4. Ikterus pada sumbatan duktus kholedokhus .

Any increase in plasma bilirubin above 20mg/dL is considered dangerous in neonates. . However. The latter is the result of inherited deficiencies in the enzyme responsible for bilirubin conjugation to glucuronic acid. Kernicterus occurs in infants with severe unconjugated hyperbilirubinemia and in young adults with high serum levels of unconjugated bilirubin. individual differences in bilirubin sensitivity can result in kernicterus at lower bilirubin levels. bilirubin UDP glucuronyl transferase (bilirubin-UGT). Bilirubin toxicity Bilirubin toxicity (bilirubin encephalopathy) can be life threatening in neonates. Bilirubin encephalopathy is characterized by yellow discoloration of the basal ganglia in babies with intense jaundice (first described over a century ago and called "kernicterus".

2. uncouple oxidative phosphorylation. electron transport proteins. enzymes of RNA synthesis. a variety of different classes of enzymes (dehydrogenases. 4. hydrolyases. Bilirubin impacts Bilirubin has been shown to inhibit : 1. DNA synthesis. 3. ATPase activity in brain mitochondria. . All of these toxic effects of bilirubin are reversed by binding to albumin. protein synthesis and carbohydrate metabolism.

Inherited disorders in bilirubin metabolism 1. . 2. conjugated hyperbilirubinemias are less severe in their symptomology than are the unconjugated hyperbilirubinemias. bilirubin is water soluble. Gilbert syndrome and the Crigler-Najjar syndromes result from predominantly unconjugated hyperbilirubinemia. therefore. Once conjugated to glucuronate. Dubin-Johnson syndrome and Rotor syndrome result from conjugated hyperbilirubinemia.