42 - Heme Biosynthesis & Breakdown Flashcards
FERROCHELETASE
LAST/4th step in Heme Biosynthesis
occurs in SEVERAL steps
contains 2 Iron-Sulfur Cluster = Fe-S Cluster
adds IRON –> Protoporphyrin IX
HEME
HO-2
Physiological Properties
- *Constitutive**
- *OXYGEN SENSING**
MORE FUNCTIONAL as an ANTIOXIDANT
under Oxidative stress conditions
- *neuroprotection**
- *neovascularization**
Nitric Oxide effect on HEME Proteins
sGC = Soluble Guanaline Cyclase
NO –> ENHANCE ACTIVITY of HEME protein
- *CYP450**
- *NO –> decrease activity of heme protein**
UroPorphyrinogen 3 Synthase
3rd step in Heme biosynthesis
“FLIPPING & CLOSURE”
Linear hydroxymethylbiline
VVVV
macrocyclic Urophohyrinogen 3
- is also a precursor for the synthesis of*
- *Vit B12 / Chlorophyll** / Heme
What are GASOTRANSMITTERS?
Gaseous molecules that are
used to TRANSMIT Chemical Signals
- *Nitric Oxide** = NO
- *Carbon Monoxide** = CO
- *Hydrogen Sulfide** = H2S
all are known to be TOXIC
BUT @ tiny concentrations = key to signaling/regulatory fxn
highly reactive & used up quickly
DNIC
how is it formed?
NITRIC OXIDE + Chelatable Iron Pool CIP
DNIC is an
indicator of LESS IRON
because the IRON POOL is being DEPLETED by reactions with NO
Adding NO –> taking away iron
HO-1
Heme Oxygenase
INDUCIBLE isoform
Induced by substrate = HEME
OR
in response to STRESS:
oxidative stress / hypoxia / heavy metals / cytokines / NO
HIGHLY REGULATED
NOS
Nitric Oxide Synthase
Enzyme that synthesizes
NITRIC OXIDE
L-Arginine–>L-Citrulline+ NO
in the presence of:
Oxygen + NADPH
or
Heme + BH4 + Flavin
What is the Committed Step of
HEME BIOSYNTHESIS
- *ALA SYNTHASE**
- *rate-limiting for the overall pathway**
HEME = FEEDBACK INHIBITOR
inhibits transcription of ALA synthase
- PLP = coenzyme for ALA synthase
-
Condensation
- succenyl-coA while Glycine is in SCHIFF BASE
- produce ALA
What does NITRIC OXIDE
REACT WITH?
Under biological conditions:
METALS
like the CIP (iron) –> DNIC
or
Other Free Radicals
very complex –> reacts with MANY parts of the body
HEME BIOSYNTHESIS
PATHWAY
ALA SYNTHASE
condensation reaction –> also is the RATE LIMITING step
succinyl-CoA –> ALA
PBG Synthase
Porphobilinogen Deaminase forms the pyrrole ring of PBG
Uroprphyrinogen 3 Synthase
linear tetrapyrrole hydroxymethylbilane –> UPG 3
Ferrocheletase
UPG 3 –> protoporphyrin IX + Iron = HEME
Similaraties of
CHELATORS & NITRIC OXIDE
Target & Sequester the same population of iron –> CIP
Both can also
influence CELL SIGNALING & GENE EXPRESSION
Adding NO –> take away iron
- *Carbon Monoxide**
- *Functions**
Heme –HO–> Biliverdin + Fe2+ + CO
Cell-Signaling Molecule
SMOOTH MUSCLE Relaxation
Cytoprotection
ANTI-Apoptosis
How is HO-2 REGULATED?
NO & ROS
Increase in NOS Activity –> more HO2 Activity
but it is constitutively expressed, NOT upregulated
Nitric Oxide’s effect on IRON METABOLISM
DISRUPTS FE-S Clusters
Also causes the body to THINK that we are IRON STARVED
because NO + CIP = DNIC
IRP2 STABILIZATION
MORE NO –> less CIP –> try in INCREASE CIP
and vice versa
