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Metabolism > Haem metabolism > Flashcards

Haem metabolism Flashcards

1
Q

importance of haem

A
  • oxygen transport and storage (haemoglobin, myoglobin)
  • oxygen metabolism (oxidases, peroxidases, catalases, hydroxylases)
  • electrons transfer and drug metabolism (cytochromes)
  • signal transduction (nitric oxide synthase)
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2
Q

why must iron bind to haem

A

free iron is toxic

iron binds to haem and haem is always bound to protein in circulation

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3
Q

where is haem synthesised

A

most cells

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4
Q

what metabolise the largest quantities of haem

A

liver and erythron

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5
Q

how is haem transported

A

in plasma, bound to haemopexin or as haemoglobin bound to haptoglobin

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6
Q

where is the main site of haem breakdown

A

macrophages, liver

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7
Q

what is haem broken down to, and what happens next

A

bilirubin which is transported to the liver for conjugation and excretion

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8
Q

principle site of haem synthesis in all tissues

A

erythroid cells ~85%

hepatocytes ~15%

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9
Q

what is haem required for in hepatocytes

A

incorporation into cytocrhome p450

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10
Q

where is majoriy of body’s iron content

A

80% of body’s iron is incorporated into haemoglobin in developing RBC

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11
Q

overview of haem biosnythesis

A
  • 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
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12
Q

Rate limiting step of haem biosynthesis

A

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

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13
Q

ALAS

A

aminolevuninc acid synthase

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14
Q

what is the rate limiting enzyme of haem biosynthesis

A

ALAS

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15
Q

Where does haem biosynthesis begin and with what

A

in the mitochondria with glycine and succinyl CoA

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16
Q

basis of haem biosythesis

A
  • 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
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17
Q

ALA

A

Aminolevulinic acid

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18
Q

ALAS

A

Aminolevulinic acid synthetase = rate limit step

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19
Q

ALAD

A

Aminolevulinic acid dehydrate (2x)

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20
Q

PBDG

A

porphobilinogen deaminase
(4x)
deamination

21
Q

URO32

A

uropophyrinogen III sythetase

-cyclisation of HMB

22
Q

UROD

A

uropophyrinogen III decarboxylase

  • change in side chains
  • removal of 4 carboxylic groups of the acetic side chains AKA decarboxylation of methyl groups
23
Q

CPO

A

copropophyrinogen oxidase
- oxidative carboxylation of propionate groups of pyrrole rings A and B
AKA 2 propionate groups -> 2 vinyl groups

24
Q

PPO

A
  • protoporphyrinogen oxidase
  • in mitochondria
  • oxidisation
25
Q

FECH

A
  • Ferrocheletase
  • insertion of iron in protoporphyrin ring
  • in mitochondrion
    = haem
26
Q

types of ALA synthase in mammals

A

regulation of haem biosynthesis in mammals occurs via 2 distinct pathways

  • nonerythroid cells
  • erythroid precursor cells
27
Q

regulation of haem biosynthesis in non-erythroid cells

A

housekeeping = ALAS-1

  • transcriptional regulation via haem
  • also reguation of mitochondiral import of ALAS by haem - direct inhibition of the enzyme by haem
28
Q

regulation of haem biosynthesis in erythroid cells

A

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
29
Q

regulation of haem synthesis

A
  • 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
30
Q

why is regulation of haem synthesis important

A

if excess haem produced, degradation occurs which willl release free iron causing iron toxicity

31
Q

how is haem degraded

A
  • 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
32
Q

what is HO-1

A

Heam-oxygenase-1

enyme from the endoplasmic reticulum which oxidises haem ring to open it, as part of degradation

33
Q

ferric iron

A

Fe 3+

34
Q

what happens to bilirubin produced by haem degradation

A
  • 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
35
Q

biological activity of reaction products from haem degradation

A
  • CO has anti-inflamatory, anti-thrombotic and anti-apoptopic effects
  • biliverdin and bilirubin have anti-oxidant properties
36
Q

what are porphyrias

A

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
37
Q

classification of porphyrias

A
  • hepatic
  • erythropoetic
  • acute hepatic
  • cutaneous porphyrias
38
Q

acute hepatic porphyrias

A

clinical characteristics: neurological disturbances

biochemical characteristics: an overproduction of porhyprin precursos ALA and PBG

39
Q

porphoryn precursos

A

ALA and PBG

40
Q

cutaneous porphyrias

A

clinical characteristics: cutaneous photosensitivty

biochemically characteristics: excessive production of porphorias

41
Q

Acute Intermittent Porphyria (AIP)

A
  • 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
42
Q

Porphyria Cutanea Tarda (PCT)

A
  • most common of all forms of the porphyrias
  • heterogenous group of cutaneous porphyric diseases due to UROD deficience
  • inherited or more commonly acquired
43
Q

most common form of porphyrias

A

porphyria cutanea tarda

44
Q

what can lead to acquiring PCT

A
  • 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
45
Q

Variegate porphyria (VP)

A
  • 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
46
Q

what is elevated concentration of fecal protoporphyrin IX a biomarker for

A

Variegate porphyria (VP)

47
Q

photodynamic theory

A
  • 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
48
Q

Cellular iron metabolism is regulated through the IRE/IRP system, which acts at the level of

A

translation

Metabolism (11 decks)

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