42 - Heme Biosynthesis & Breakdown

Question 1

FERROCHELETASE

Answer 1

LAST/4th step in Heme Biosynthesis
occurs in SEVERAL steps

contains 2 Iron-Sulfur Cluster = Fe-S Cluster

adds IRON –> Protoporphyrin IX

HEME

Question 2

HO-2
Physiological Properties

Answer 2

• *Constitutive**
• *OXYGEN SENSING**

MORE FUNCTIONAL as an ANTIOXIDANT
under Oxidative stress conditions

• *neuroprotection**
• *neovascularization**

Question 3

Nitric Oxide effect on HEME Proteins

Answer 3

sGC = Soluble Guanaline Cyclase
NO –> ENHANCE ACTIVITY of HEME protein

• *CYP450**
• *NO –> decrease activity of heme protein**

Question 4

UroPorphyrinogen 3 Synthase

Answer 4

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

Question 5

What are GASOTRANSMITTERS?

Answer 5

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

Question 6

DNIC
how is it formed?

Answer 6

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

Question 7

HO-1
Heme Oxygenase​

Answer 7

INDUCIBLE isoform

Induced by substrate = HEME
OR
in response to STRESS:
oxidative stress / hypoxia / heavy metals / cytokines / NO

HIGHLY REGULATED

Question 8

NOS
Nitric Oxide Synthase

Answer 8

Enzyme that synthesizes
NITRIC OXIDE
L-Arginine–>L-Citrulline+ NO

in the presence of:
Oxygen + NADPH
or
Heme + BH4 + Flavin

Question 9

What is the Committed Step of
HEME BIOSYNTHESIS

Answer 9

• *ALA SYNTHASE**
• *rate-limiting for the overall pathway**

HEME = FEEDBACK INHIBITOR
inhibits transcription of ALA synthase

1. PLP = coenzyme for ALA synthase
2. Condensation
   
   1. succenyl-coA while Glycine is in SCHIFF BASE
3. produce ALA

Question 10

What does NITRIC OXIDE
REACT WITH?

Answer 10

Under biological conditions:
METALS
like the CIP (iron) –> DNIC
or
Other Free Radicals

very complex –> reacts with MANY parts of the body

Question 11

HEME BIOSYNTHESIS
PATHWAY

Answer 11

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

Question 12

Similaraties of
CHELATORS & NITRIC OXIDE

Answer 12

Target & Sequester the same population of iron –> CIP

Both can also
influence CELL SIGNALING & GENE EXPRESSION

Adding NO –> take away iron

Question 13

• *Carbon Monoxide**
• *Functions**

Answer 13

Heme –HO–> Biliverdin + Fe2+ + CO

Cell-Signaling Molecule

SMOOTH MUSCLE Relaxation

Cytoprotection

ANTI-Apoptosis

Question 14

How is HO-2 REGULATED?

Answer 14

NO & ROS

Increase in NOS Activity –> more HO2 Activity

but it is constitutively expressed, NOT upregulated

Question 15

Nitric Oxide’s effect on IRON METABOLISM

Answer 15

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

Question 16

Porphobilinogen Deaminase

Answer 16

• *2nd** step in heme Biosynthesis
• *PBG Synthase**

2x ALA –> Porphobilinogen = PBG
VVVV
4x PBG –> Porphyrin Ring
VVVV
PBG added to dipyrromethane until…
VVVVV
LINEAR HEXAPYRROLE

Question 17

HO-2
heme oxygenase 2

Answer 17

CONSTITUTIVE isoform

expressed under HOMEOSTATIC conditions

mainly found in the:
BRAIN & TESTES

Induced by GRE
glucocorticoid Response element

Question 18

NITRIC OXIDE
GENERAL FACTS

Answer 18

Short biological half life = 0.1-2 seconds

formed by NOS enzymatically in our body
uncharged / soluble / diffusible

Vascular Tone / Host Defense / Memory

Pharmacology:
NITROGLYCERIN / NITROPRUSIDE
NO-NSAIDS

Question 19

NITRIC OXIDE –> sGC

Answer 19

increases acivity of SGC by 200x
soluble guanylate cyclase
an also be activated by CO

VASODILATION / BRONCHODILATION

Question 20

Similarities of

HO-1 & HO-2

Answer 20

UBIQUITOUSLY EXPRESSED
but HO-2 –> testes/brain mainly
HO2 –> Spleen / Liver / bone marrow
&
Catalytically active
use HEME as a substrate & cofactor

DIFFER IN PHYSIOLOGICAL PROPERTIES

Question 21

HMOX1

Answer 21

Gene that encodes HO-1 (inducible heme oxygenase)
found in the ER / Mitochondria / nucleus

HIGHLY EXPRESSED in tissues involved in the
degradation of senescent RBC’s:
Spleen / Liver / bone Marrow
enzyme is expressed in mononuclear phagocytes

Question 22

What supplies ELECTRONS for
HEME OXYGENASES?

Answer 22

CYP450 REDUCTASE
provides
NADPH

for heme catabolism

• *Heme** – HO + NADPH –> Biliverdin 9
• *happens TWICE**

Question 23

HO-1
Physiological Properties

Answer 23

• *INDUCIBLE**
• *Iron Homeostasis**

ERYTHROPOIESIS

IMMUNITY
innate & adaptive

Mitochondrial fxn