HEME METABOLISM
Professor Dr.V.Meera M D DGO
RED COLOR OF BLOOD IS
ATTRIBUTED TO……..!
PIGMENT HEME PRESENT AS Hb IN
RBCs
HEME SYNTHESISED FROM
DEGRADATION OF HEMOGLOBIN
HEMOPROTEINS
Non-erythroid Erythroid
Haemoproteins Haemoglobin
HEME – METALLOPORPHYRIN
ferrous iron atom
co-ordinated in
the center of
tetrapyrrole ring
of protoporphyrin
PORPHYRINS
NATURAL PORPHYRINS-
SUBSTITUTENT SIDE CHAINS
ON PORPHYRIN NUCLEUS
UROPORPHYRINS
ACETATE & PROPIONATE SUBSTITUENTS
TYPE I TYPE III
(Symmetric
. substitution) (Asymmetric substitution)
COPROPORPHYRINS
METHYL & PROPIONATE SUBSTITUENTS
TYPE I TYPE III
(Symmetric arrangement (Assymetric arrangement
.
of substituent) of substituent)
tion)
TYPE I &III are found in nature.
TYPE III- more abundant & more important
(includes HEME)
HEME & PROTOPORPHYRIN IX
METHYL,VINYL & PROPIONATE
SUBSTITUENTS
TYPE III PORPHYRINS
(Asymmetric arrangement of
substitution)
.
Reticulo endothelial System
Proerythroblasts and erythroblasts account
for most of the synthesis
As cells mature to reticulocytes – Hb
synthesis is reduced
Mature human erythrocytes lose all ability
to synthesize Hb
HEME BIOSYNTHESIS
SITES: ALL NUCLEATED CELLS
MATURE RBCS – NO MITOCHONDRIA – NO SYNTHESIS
MAJOR:
ERYTHROCYTE PRECURSOR CELLS OF BONE
MARROW – ACTIVE IN Hb SYNTHESIS- 85%
LIVER : HEME PROTEINS – CYTOCHROME P450 –
(MAJORITY OF THE REMAINDER15%)
HEME SYNTHESISED FROM
SUCCINYL CoA &GLYCINE
) MITOCHONDRIA
ALA SYNTHASE
INDUCIBLE ENZYME
Induced by fasting and drugs – barbitutates,
OCP, Steroids,Griseofulvin & Hydantoins
Subject to repression by free heme
HEMIN DECREASES ACTIVITY OF
HEPATIC ALA SYNTHASE
CYTOPLASM
STEP 3: Synthesis of HMB
CYTOPLASM
/ HMB Synthase /
Uroporphyrinogen I
Synthase
STEP 4: Synthesis of Uroporphyrinogen III
Both UROPORPHYRINOGENS have Methylene bridges(-CH2-).
DONOT FORM Conjugated ring systems hence colourless.
Autooxidation to their respective coloured porphyrins(catalysed
by light)
CERTAIN PORPHYRIAS NORMAL CONDITIONS
STEP 5: Synthesis of CPG
CYTOPLASM
This enzyme also acts on Uroporphyrinogen I
STEP 6: Synthesis of PPG
MITOCHONDRIA
Mammalian liver- conversion requires molecular oxygen.
This enzyme also only on Coproporphyrinogen III
(NO TYPE I PROTOPORPHYRINS IN NATURE)
STEP 7: Synthesis of PP
MITOCHONDRIA
STEP 8: Genaration of Heme
MITOCHONDRIA
Last 3 enzymes and the first enzyme –
CPG oxidase
PPG oxidase MITOCHONDRIAL
Ferrochelatase and
ALA synthase(FIRST ENZYME)
Other enzymes are cytosolic
Both erythroid and non-erythroid forms
ALAS of are found.
REGULATION OF HEPATIC
HEME SYNTHESIS
ALA Synthase is the committed step of the
hepatic heme synthesis pathway, & is usually
rate-limiting for the overall pathway.
2 ISOFORMS OF ALAS –ALAS1 (hepatic) &
ALAS2(erythroid)
Regulation
1.Short Term: ALAS is allosterically
inhibited by hematin
2. Long Term:
Regulation occurs through control of gene
transcription.
Heme functions as a feedback inhibitor,
repressing transcription of the ALA Synthase
gene in most cells.
Heme – acts as co-repressor & combines with
aporepresssor molecule and acts as negative
regulator of ALAS1.
Half life of ALAS1 is1hr.
Heme also affects translation of the enzyme
and its transfer from Cytosol to the
Mitochondria
Comparmentalisation of enzymes of
heme synthesis- makes the regulation
easier.
Lead-inhibits ALA dehydratase and
ferro chetalase (excretion of ᵟ-ALA
&protoporphyrin in urine
INH-antitubercular drug- Decreases the
availability of Pyridoxal phosphate
High concentration of glucose- prevents
induction of ALA synthase (forms the basis
for treatment to relieve acute attacks of
porphyrias)
Many drugs (barbiturates)upon administration
Metabolised by a system that utilises
hemo-protein (cytochrome p450)
Reduced intracellular heme concentration
Effects derepression of ALAS1
Increased rate of heme synthesis
to meet cells needs
REGULATION OF ERYTHROID
FORMS OF ALAS2
NOT INDUCED BY DRUGS
NO FEEDBACK REGULATION BY
HEME
HEME SYNTHESIS IS UNDER THE
CONTROL OF ERYTHROPOIETIN AND
THE AVAILABILITY OF
INTRACELLULAR IRON
PORPHYRINS ARE COLORED &
FLUORESCE
Absorption curve –for a solution of
porphyrin +5%Hcl produces sharp
absorption band near 400nm
SORET BAND
• Porphrins-dissolved in mineral acids/organic
solvents--- illuminated by UV light ----they
emit red fluorescence.
Small amounts of free porphyrins can be
detected.
Double bonds – absorption & fluorescence
APPLICATION OF PHOTODYNAMIC
PROPERTY OF PORPHYRINS CANCER
PHOTOTHERAPY
hematoporphyrin/other related compounds----tumor
cells takes up more porphyrins--- exposed to argon
laser--- excites the porphyrins--- cyototoxic effects
Spectrophotometry is used to test for
porphyrins & their precursors
These compounds- found in
urine/feces.
Seperated from each other
by extraction with appropriate
solvent mixtures.
Identified and quantified
