HEME SYNTHESIS

&
PORPHYRIAS
 MCI COMPETENCY

• Describe the functions of haem in the body

and describe the processes involved in its
metabolism and describe porphyrin
metabolism
Specific Learning Objectives
Learning Objectives

The learner will be able to:

• Outline the structure of porphyrins and heme
• Trace pathway of biosynthesis of heme
• Classify porphyrias and differentiate hepatic and
erythropoetic porphyrias
• Enumerate the salient clinical features and management
of each type
 OUTLINE
• Pyrolles , Pophyrins, Porphyrinogens
• Heme : Def , Functions , hemo compounds
• Heme synthesis : substrate , location , stages ,
steps , regulation
• Porphyrias : def , types , important porphyrias
Pyrrole ring
 Pyrole
• Large , flat , heterocyclic , 5 membered ring
structure containing nitrogen with conjugated
double bond & aromatic characterstics
 Porphyrins
• Cylic compounds composed of 4 pyrrole rings
held by methyne bridges
• Properties : basic ,orange , soluble , absorb
light , flouresence , chelate metal
• Types : I & III
Porphyrin Ring
Porphyrins of Biological Importance
Name of Porphyrin Order of substituents from 1st
to 8th positions

Uroporphyrin I A,P, A,P, A,P, A,P

Uroporphyrin III A,P, A,P, A,P, P,A

Coproporphyrin I M,P, M,P, M,P, M,P

Coproporphyrin III M,P, M,P, M,P, P,M

Protoporphyrin III M,V, M,V, M,P, P,M

(A = acetyl; P = propionyl; M =
methyl; V = vinyl)
Structure of HemeH
 HEME
• Def : A iron containing
metalloporphyrin
• forms prosthetic group
of hemproteins
• Functions : Transport
gas
Cofactor for enzymes
Role in ETC
Colour of Hb
• Heme is present in
a. Hemoglobin
b. Myoglobin
c. Cytochromes
d. Peroxidase
e. Catalase
f. Tryptophan pyrrolase
g. Nitric oxide synthase
 HEME Synthesis
• Site : Cytosol , Mitochondria
• Tissues :Liver , RBC
• Substrate : Succinyl CoA , Glycine
• 3 Stages .i. Synthesis of ALA.
ii .Synthesis of Protoporpyrinogen IX
iii .Synthesis of Heme
1 : Haem synthesis
st
 Compartmentalization of enzymes of heme synthesis.
Part of synthesis is in mitochondria, and the rest in cytoplasm.
 REGULATION OF SYNTHESIS
• RLE : ALA synthase .Heme , drugs , alcohol , lead
• Heme inhibits ALA synthase , ALA dehydratase
,Ferrochelatase
Heme acts by Feedback inhibtion , repression ,
tranport inhibition of ALA synthase
• ↑ :Steroids , alcohol , drugs , insecticides ,
carcinogens, hypoxia
• ↓:Lead , INH , Heme
Enzyme deficiencies in
porphyrias
 PORPHYRIAS
• Def : Group of disorders resulting from
enzyme deficiencies of heme synthesis
pathway .
• Genetic or acquired
• Porphyrins or its precursors are increased in
blood & excreted in urine
• E.g : Acute intermittent porphyria
 Acute intermittent porphyria
• Synonym : Intermittent acute porphyria ,
Paroxysmal porphyria
• ABR : IAP
• Def :
• Enzyme deficiency :PBG deamianse
• PBG UP III
• Blood : ↑ PBG & ALA
• Urine : Darkens on standing
 Acute intermittent porphyria
• Onset : After puberty
• Precipitated : Infection , stress
• CF : GIT : Abdominal pain , vomiting
CNS :seizures , depression , paraesthesia
CVS :tachycaria , hypertension
Treatment : Haematin
 Porphyria Cutanea Tarda
• Def : a form of porphyria that primarily affects
the skin.
• Enzyme deficiency :
Uroporphyrinogendecarboxylase
• UP III CP III
• Blood : Uroporphyrins , PBG , ALA
• Urine : Uroporphyrins →red flouresence
• Clinical features : Photosensitivty
 Variegate Porphyria
• Synonym : Mixed or combined porphyria
• Def : a inherited porphyria which affects git ,
skin & cns .
• Deficiency : Protoporphyrin
oxidase ,Ferrocheletase
• Blood & Urine : all porphyrins
• CF : GIT , CNS , Cutaneous
• Urine : coloured
 ACQUIRED
• Toxic porphyria
• Drugs[barbitone], toxic compounds [lead ]
• Disease [ cirrhosis , anaemia , leukemia ]
• ↓ :ALA dehydratase,UP I synthase,
Ferrochelatase
• Abnormality : Coproporphyrins
Summary Of Major Features Of Porphyrias
Porphyria Cutanea Tarda

Note the skin lesions due to photosensitivity

• Treatment:
– Symptomatic
– Avoid drugs that induce cyt P450
– Glucose _loading
– Hematin administration
– β carotenePhotosensitivity decreases
MCI Competency
 RGUHS
• SHORT ESSAYS
• Heme synthesis (regulation).
• Porphobilinogen.
• What are Porphyrias. How are they classified.
Name the enzymatic defect & biochemical
findings in any one of them .
• What is pophyria . Mention the defect , signs &
symptoms of Acute intermittent porphyria
• Congential erythropoietic porphyria
 • SHORT ANSWERS
• Name the levels at which heme synthesis is
regulated
• AIP
• Name 2 porphyrias & enzyme defect in them
Features of important types of porphyrias

Type Enzyme Inheri- Excretion in Other salient features

defect tance urine
Hereditary CPG-III- Auto- UP and CP Symptoms similar to
copro- oxidase somal excreted in AIP; but milder.
porphyria (enzyme 5) domina urine and Photosensitivity is also
nt feces. Colored seen.
urine.
Hereditary Heme Auto- Neither Protoporphyrin
proto- synthase or somal porphyrins nor increased in plasma,
porphyria Ferro- domi- precursors are RBCs and feces. RBCs
chelatase nant excreted in show fluorescence.
(enzyme 7) urine.
Features of Important Types of Porphyrias

Type Enzyme defect Inheri- Excretion in Other salient features

tance urine
Acute inter- PBG- Auto-somal Precursors, ALA Most common porphyria (1
mittent deaminase domi-nant and PBG. No in 10,000). Hepatic
porphyria (UPG-1 color on voiding porphyria. Abdominal and
(AIP) synthase) neurological manifestations.
(enzyme 3) No photosensitivity.

Congenital UPG- Auto-somal UP and CP; Port- Marked photosensitivity.

erythro- cosynthase rece-ssive wine Erythrodontia. Incidence,
poietic (enzyme 3b) appearance rare.
porphyria
Porphyria UPG- Auto-somal Uroporphy-rins. Second most common;
cutanea decarboxy-lase domi-nant Urine colored. incidence 1 in 25,000.
tarda (enz 4) Photosensitivity.
Diagnosis of Porphyrias with Neurovisceral Manifestations

Disease and enzyme defect Laboratory findings

ALAD-porphyria; Urine ALA ++
(ALA dehydratase Urine PBG normal
deficiency)(Enz 2) RBC HMBS normal
AIP (HMBS or PBG Urine ALA ++
Deaminase Urine PBG ++
(Enzyme 3) Plasma porphyrins normal
HCP; Coproporphy- Urine ALA normal
rinogen oxidase Urine PBG ++
deficiency,Enz 5 Plasma porphyrins normal
VP; Protoporphyrinogen oxidase Urine ALA normal
deficiency Urine PBG +++
(Enzyme 6) Urine porphyrins ++
Plasma porphyrins ++
ALA = amino levulinic acid; ALAD = amino levulinic acid dehydratase; PBG =
porphobilinogen; HMBS = hydroxymethyl bilane synthase (PBG deaminase); AIP
= acute intermittent porphyria; HCP = hereditary coproporphyria; VP = variegate
porphyria.
 2 : Globin synthesis
nd

• Humans normally carry 8 functional globin

genes, arranged in two duplicate gene
clusters:
• The β-like cluster on the short arm of
chromosome 11.
• The α-like cluster on the short arm of
chromosome 16.
• These genes code for 6 different types of
globin chains: α,β,γ,δ,ε,ζ, globin.
2 : Globin synthesis
nd
 Ontogeny of globin synthesis
Type of Hb Type of Globin Region Time
Gene

Hb Gawer1 ζ ζ&ε Yolk Sac weeks of 3

) ε)2 Gestation

Hb Portland(ζ γ)2 γ&α Yolk Sac 5 weeks of

Hb GawerII (αε)2 Gestation

Hb F (α γ)2 α & γ& β Liver & spleen weeksof 6-30

Gestation

Hb A2 (α δ2( δ Liver weeks of 30

Gestation

HbA(α β)2 ___ B.M At Birth

(Continues…
…Continued)

Biosynthesis of heme.