Short slides for heme Biosynthesis and Porphyrias related to Heme pathway

1. HEME BIOSYNTHESIS
&
PORPHYRIAS
in short
Dr. Deepa Anantha Laxmi N.V

2. MITOCHONDRIA CYTOSOL
HEME BIOSYNTHESIS
4 STEPS IN
MITOCHONDRIA
AND 4 STEPS IN
CYTOSOL

3. HEME
• HEME Or iron porphyrin IX is a part of many compounds
• Hemoglobin
• Myoglobin
• Respiratory cytochromes
• Peroxidase
• Cytochromes P450
• Catalase
• Tryptophan pyrrolase, and
• Nitric oxide synthase

4. HEME BIOSYNTHESIS PATHWAY AND PORPHYRIAS
• The eight enzymatic steps involved in heme biosynthesis pathway
• The 1st and last three- 6th, 7th and 8th steps in the pathway are carried out in the
mitochondria while the intermediate four steps are performed in the relatively
reducing environment of the cytosol.
• Pathology in heme biosynthesis leads to disorders known as Porphyrias (8 in number).
• The name porphyria is from the Greek term πορφύρα, porphyra, meaning "purple“,
• Descriptively used to refer to the colour of urine in these disorders.

5. HEME BIOSYNTHESIS PATHWAY AND PORPHYRIAS

6. TYPES OF PORPHYRIAS
Type Name Inheritance
Gene
affected
Chromosom
al location
Comments
Acute
or Inducible
Porphyrias
ALA DEFICIENCY
PORPHYRIA
AR Pbgs 9q34
Very rare severe
disease in infancy
ACUTE
INTERMITTENT
PORPHYRIA
AD Hmbs 11q23.3 Most severe form
HERIDITARY
COPROPORPHYRIA
AD Cpox 3q12
May also have
cutaneous
features
VARIEGATED
PORPHYRIA
AD Ppox 1q22
May also have
cutaneous
features

7. TYPES OF PORPHYRIAS
Type Name Inheritance Gene affected
Chromosomal
location
Comments
Cutaneous
Chronic
Porphyrias
CEP AR Uro3 10q26.1-q26.2
Rare usually manifests
itself in
infancy/childhood
HEP AR Urod 1p34.1
Rare usually manifests
itself in
infancy/childhood
PCT (Type I) Acquired None Diseases of adults
PCT (Type II) AD Urod 1p34.1
Requires additional
defects
EPP AR Fech 18q21.31
Common; onset in
infancy
XLPP X-linked Alas1 Xp11.21
Gain of function
mutations

8. TYPES OF PORPHYRIAS
Type Name Inheritance Gene affected
Chromosomal
location
Comments
Acute Hepatic
Porphyrias
ALADP AR Pbgs 9q34
Very rare
severe disease
in infancy
AIP AD Hmbs 11q23.3
Most severe
form
HCP AD Cpox 3q12
May also have
cutaneous
features
VP AD Ppox 1q22
May also have
cutaneous
features

9. TYPES OF PORPHYRIAS
Type Name Inheritance Gene affected
Chromosomal
location
Comments
Chronic Hepatic
Porphyrias
PCT (Type I) Acquired None Diseases of adults
PCT (Type II) AD Urod 1p34.1
Requires
additional defects
HEP AR Urod 1p34.1
Rare usually
manifests itself in
infancy/childhood
Erythropoietic
Porphyrias
CEP AR Uro3 10q26.1-q26.2
Rare usually
manifests itself in
infancy/childhood
EPP AR Fech 18q21.31
Common; onset
in infancy

10. DIAGNOSIS OF PORPHYRIA
Type of
porphyria
Enzyme defect Urine Stool Plasma Rbcs
X-linked
protoporphyria
ALA synthase-2
(gain of
function)
Normal PROTO PROTO Zn PROTO
ALA dehydratase
deficiency (ADP)
ALA dehydratase COPRO ALA Normal ALA Zn PROTO
Acute
intermittent
porphyria (AIP)
PBG deaminase ALA, PBG, URO I Normal COPRO I ALA, PBG, URO I ↓PBGD
Congenital
erythropoietic
porphyria (CEP)
Uroporphyrinog
en III synthase
(cosynthase)
COPRO I URO I COPRO I COPRO I URO I COPRO I URO I

11. DIAGNOSIS OF PORPHYRIA
Type of
porphyria
Enzyme defect Urine Stool Plasma Rbcs
Porphyria
cutanea tarda
(PCT) and
Hepatoerythropo
ietic porphyria
(HEP)
Uroporphyrinoge
n III
decarboxylase
Uroporphyrin,
heptacarboxyl
porphyrin
Heptacarboxyl
porphyrin
ISOCOPRO
Uroporphyrin,
heptacarboxyl
porphyrin
Zn PROTO
Hereditary
coproporphyria
(HCP)
Coproporphyrino
gen III oxidase
ALA, PBG,
COPRO III
COPRO III COPRO Normal
Variegate
porphyria (VP)
Protoporphyrino
gen oxidase
ALA, PBG,
COPRO III
PROTO COPRO III
Porphyrin
peptide
conjugate
Normal
Erythropoietic
protoporphyria
(EPP)
Ferrochelatase
COPRO III with
hepatopathy
PROTO PROTO PROTO

12. REFERENCES
• Harrison’S Internal Medicine
• Articles:
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4279155/
• https://www.sciencedirect.com/science/article/abs/pii/S1096719218
305869

13. THANK YOU