Haem metabolism Flashcards
importance of haem
- oxygen transport and storage (haemoglobin, myoglobin)
- oxygen metabolism (oxidases, peroxidases, catalases, hydroxylases)
- electrons transfer and drug metabolism (cytochromes)
- signal transduction (nitric oxide synthase)
why must iron bind to haem
free iron is toxic
iron binds to haem and haem is always bound to protein in circulation
where is haem synthesised
most cells
what metabolise the largest quantities of haem
liver and erythron
how is haem transported
in plasma, bound to haemopexin or as haemoglobin bound to haptoglobin
where is the main site of haem breakdown
macrophages, liver
what is haem broken down to, and what happens next
bilirubin which is transported to the liver for conjugation and excretion
principle site of haem synthesis in all tissues
erythroid cells ~85%
hepatocytes ~15%
what is haem required for in hepatocytes
incorporation into cytocrhome p450
where is majoriy of body’s iron content
80% of body’s iron is incorporated into haemoglobin in developing RBC
overview of haem biosnythesis
- highly conserved process
- 8 enzymes
- 4 in the mitochondira
- 4 in the cytoplasm
- synthesis starts in the mitochondria
- metabolite moves out into the cytoplasm
- finishes in the mitochondria
Rate limiting step of haem biosynthesis
Conversion of
succinyl CoA + Glycine –> aminolevulinic acid
- by action of ALAS enzyme (hence rate limiting)
succinyl CoA and glycine are in the mitochondria
aminolevulinic acid moves out to cytoplasm
ALAS
aminolevuninc acid synthase
what is the rate limiting enzyme of haem biosynthesis
ALAS
Where does haem biosynthesis begin and with what
in the mitochondria with glycine and succinyl CoA
basis of haem biosythesis
- glycine + succinyl CoA -> ALA
enzyme: ALAS
location mitochondria - ALA -> Porphobilinogen
enzyme: ALAD
location: cytoplasm - Porphobilinogen -> hydroxymethylbilane
enzyme: PBDG - hydroxymethylbilane -> Uroporphyrinoegn III
enzyme: URO3S - Uroporphyrinoegn III -> coproporphyrinoegn III
enzyme: UROD
-coproporphyrinoegn III -> protoporphyrinogen IX
enzyme: CPO
location: mitochondria - protoporphyrinogen IX -> protoporhyrin IX
enzyme: PPO
-protoporhyrin IX -> HAEM
enyzyme: FECH
ALA
Aminolevulinic acid
ALAS
Aminolevulinic acid synthetase = rate limit step
ALAD
Aminolevulinic acid dehydrate (2x)
PBDG
porphobilinogen deaminase
(4x)
deamination
URO32
uropophyrinogen III sythetase
-cyclisation of HMB
UROD
uropophyrinogen III decarboxylase
- change in side chains
- removal of 4 carboxylic groups of the acetic side chains AKA decarboxylation of methyl groups
CPO
copropophyrinogen oxidase
- oxidative carboxylation of propionate groups of pyrrole rings A and B
AKA 2 propionate groups -> 2 vinyl groups
PPO
- protoporphyrinogen oxidase
- in mitochondria
- oxidisation
FECH
- Ferrocheletase
- insertion of iron in protoporphyrin ring
- in mitochondrion
= haem
types of ALA synthase in mammals
regulation of haem biosynthesis in mammals occurs via 2 distinct pathways
- nonerythroid cells
- erythroid precursor cells
regulation of haem biosynthesis in non-erythroid cells
housekeeping = ALAS-1
- transcriptional regulation via haem
- also reguation of mitochondiral import of ALAS by haem - direct inhibition of the enzyme by haem
regulation of haem biosynthesis in erythroid cells
eALAS = ALAS-2
- translational regulation
- iron responsive element (IRE) located in the 5’ end of mRNA
- iron regulatory protein (IRP) interact with IRE and inhibit translation
regulation of haem synthesis
- feedback mechanism is important
- Inhibition of ALAS is well established
- transcriptional control by heam indicated, as well as control of mitochondrial import
- need to coordinate iron supply in erythroid cells
- 5’ IRE on eALAS mRNA
- other mechanisms are important but not well understood
why is regulation of haem synthesis important
if excess haem produced, degradation occurs which willl release free iron causing iron toxicity
how is haem degraded
- haem is oxidised which opens the ring by, by action of ER enzyme HO-1
- oxidation occurs on specific carbon producing the liner tetrepyrole biliverdin, ferric iron (Fe3+) and CO
- tetrepyrole biliverdin reduced to bilirubin
what is HO-1
Heam-oxygenase-1
enyme from the endoplasmic reticulum which oxidises haem ring to open it, as part of degradation
ferric iron
Fe 3+
what happens to bilirubin produced by haem degradation
- bilirubin conjugated with gucuronic acid = bilirubin diglucuronide and excreted in the bile
- some is reabsorbed and excreted in urine = yellow
- rest is metabolised in colon by bacteria; intestinal bacteria metabolise bilirubin to urobilirubin
biological activity of reaction products from haem degradation
- CO has anti-inflamatory, anti-thrombotic and anti-apoptopic effects
- biliverdin and bilirubin have anti-oxidant properties
what are porphyrias
group of disorder caused by deficiencies in the activity of enzymes within haem biosynthesis pathway
- porphorias and/or their precursos (ALA, PBG) are abnormall produced in excess and accumulate in tissues and are excreted in urin and stool
- purple, red pigment
classification of porphyrias
- hepatic
- erythropoetic
- acute hepatic
- cutaneous porphyrias
acute hepatic porphyrias
clinical characteristics: neurological disturbances
biochemical characteristics: an overproduction of porhyprin precursos ALA and PBG
porphoryn precursos
ALA and PBG
cutaneous porphyrias
clinical characteristics: cutaneous photosensitivty
biochemically characteristics: excessive production of porphorias
Acute Intermittent Porphyria (AIP)
- partial porphbilinogen deaminase (PBDG) deficiency
- Triggered by drugs that induce agents hepatic cyctochrome p450
- Causes a reduced haem level which disrupts regulation of ALAS by haem
- leads to accumulation of ALA and PBG
- neurological and psychiatric symptoms and severe abdominal pain
- reducing ALA and PBG, and excretion by intravenous heamatin injection is effective
Porphyria Cutanea Tarda (PCT)
- most common of all forms of the porphyrias
- heterogenous group of cutaneous porphyric diseases due to UROD deficience
- inherited or more commonly acquired
most common form of porphyrias
porphyria cutanea tarda
what can lead to acquiring PCT
- increased amunt of hepatic iron (HFe)
- alcohol, chlorinated cyclic hydrocarbons
- hepatitis C and/or HIV virus infections
- oestrogens
- smoking
- low vit C and carotenoid status
Variegate porphyria (VP)
- south african genetic porphyria
- heterozygouse deficiency in PPD activity
- inherited in autosomal manner
- biochemical marker is elevated concentration of fecal protoporphyrin IX
- plasma shows a fluorescnce emission when excited by long UV light
what is elevated concentration of fecal protoporphyrin IX a biomarker for
Variegate porphyria (VP)
photodynamic theory
- well established for certain skin cancers
- cells mae sensitive to light by treatment with ALA, either topically or by injection
- after time, protoporphyrin IX forms and light shone on cancer to kill cells
- can also be used for skin disorders
- being researched for treatment of other cancers
Cellular iron metabolism is regulated through the IRE/IRP system, which acts at the level of
translation
