B13 Heme metabolism Flashcards
what are the human proteins containing heme
- Mb and Hb - O2 binding function
- catalase - ROS scavenger
- NOS synthase - NO synthesis
- HO-1 (heme oxygenase) - heme degradation into billirubin
- cytochrome P450 - monooxidases for metabolic reactions containing heme cofactor
Heme functions (7)
- oxygen transport (Hb)
- oxygen storage (Mb)
- iron reservoir
- cytP450 cofactor for rections
- cellular resp and the electron shuttle of ETC
- cellular differentiation and proliferation
- signaltransduction heme - antioxidant response, circadian rhythms and microRNA processing (regulatory RNA)
why is important for heme to be regulated
bcos it contains a Fe2+ which is cytotoxic –> hence needs to be safely transported and trafficked from the site of its synthesis (mitochondria) to hemoproteins in subcellular compartments
how is heme transported and trafficked
2 COMPLEXES FORMED THAT EITHER ALLOW OR DONT ALLOW HEME EXCHANGE WITH OTHER BIOMOLECULES:
- Exhange inert heme - heme is bound in a non-dissociable manner and is inaccessible by other factors –> in this case the release/mobilisation of heme can be triggered by changing protein-protein interactions
- Labile heme - kinetically accessible –> in this case labile heme is exhanged between buffering factors (by binding to GAPDH), downstream clients like transporters OR down a thermodynamic gradient
Describe the biosynthesis of heme
- 2 succinyl coA + 2 glycine = 1 pyrrole group (this happens 4 times bcos there are 4 pyrroles in heme)
!!! using the ALAS enzyme - this step is both irreversible AND rate limiting
!! different types of pyrroles can be made depending on position of double bond + H substitution - 4 pyrrole groups –> protoporphyrin 9 (for Hb/Mb)
!! occurs through the reduction of carbon to form methine bridges + substitution of the extra groups for assymetry - Protoporphyrin 9 + Fe2+ = heme
(this happens over a series of 7 enzymatic reactions, the last one using ferrochelatase to insert ferrous iron into the protoporphyrin 9) - heme + polypeptide = Hb chain (either a or b)
- 2a + 2b chains = 1 molecule of HbA
!!! IN TOTAL: 8 ENZYMES ARE INVOLVED
Where does the heme biosynthesis occur?
MAIN TISSUES: bone marrow by erythrocytes, and liver by hepatocytes
LOCATION:
-initial reaction occurs in mitochondria IMS (to form 5-aminolevulinic acid [5-ALA])
-this is transported to the cytoplasm where the following 4 reactions occur
-the resulting molecule is moved back into the mitochondrial IMS for 1 reaction
-that molecule is transported to mitochondrial MATRIX for the final 2 reactions to make heme (through ferrochelatase as the final enzyme for Fe2+ insertion)
OVERALL: 8 enzymatic steps
What pathology results from a defect in heme synthesis?
PORPHYRIAS: defect in any of the 8 enzymes mediating the heme synthesis mechanism
:) VAMPIRE ILLNESS –> liver disorder with porphyrin buildup hence affecting skin and nervous sytem (skin rashes and production of colored porphyrins in urine)
what are the relevant isoforms of ALAS
ALAS1: ubiquitous expression
ALAS2: expressed in RBC precursor cells
!! both catalyse the first step of heme synthesis (irreversible and rate limiting) and both are controlled by Fe2+ binding elements to avoid overproduction of porphyrins (cytotoxic)
pathology arising from the defective catabolism and excretion of heme
3 TYPES OF JAUNDICE: causes a yellowish colour in the skin, mucous membranes and sclera + potentially a change in colour of urine and feces
hemolytic (higher UCB), hepatic (higher UCB and CB), obstructive (higher CB)
!! NEWBORNS: liver isnt mature enough to conjugate bilirubin bcos the UDPGT needs some time to be produced, hence an increase of BR can cause neonatal jaundice
Describe heme catabolism and excretion
- Heme degraded to biliverdin + CO + Fe2+ (via heme oxygenases - oxygen dependent)
!!! biliverdin is water soluble - Biliverdin -> bilirubin via biliverdin reductase (also uses NADPH)
What is the location of heme catabolism + excretion
- heme catabolism to bilirubin in the macrophages (bcos of their role in hemocatheresis)
- blood plasma transport (of bilirubin bound to albumin)
- hepatocytes (uptake and formation of conjugated soluble bilirubin)
- duct system and duodenum (formation of urobilirubin and urobilin)
- kidneys (excretion via urine or feces)
How is bilirubin transported and excreted?
- conjugates with albumin in blood plasma (bcos it is water insoluble) to reach hepatocytes
- uptake into hepatocytes via membrane carriers
- hepatocyte forms CONJUGATED bilirubin (soluble) by esertifying its carboxylic acid side chains with glucoronic acid / xylose or ribose (mediated by UDP-glycuronyl transferase)
- secretion of conjugated bilirubin into the bile canaliculi to raech the bile ducts and then the descending duodenum
- Conjugated bilirubin in the gut is catabolised by bacterial to form urobilinogen (colourless)
- Urobilinogen oxidised to urobilin (coloured) and is excreted in feaces and urine
What are the relevant isoforms of heme oxygenase
-part of hemoprotein family
HO-1: expressed in spleen and liver
HO-2: expressed in brain, testis and vascular system
!! they are produced by diff genes and contain 50% primary structure homology
What is the fate of the CO produced from heme catabolism
TIGHT REGULATION:
-low concs: can have advantageous effects including regulation of apoptosis, cell proliferation, inflammation and autophagy + other tissue PROTECTIVE effects
-at high concs: toxic bcos it reversibly binds to Hb and prevents O2 dissociation to tissues (hence needs to be regulated below certain levels to prevent fatal consequences)
