PORPHYRIN AND HEME
METABOLISM
• Porphyrins metal and protein
• Hemoproteins
– Heme
– Hemoglobin
• Iron
• Globin chains
• Protoporphyrin III (IX)
PORPHYRINS
HC
CH
HC
CH
N
H
Pyrrole ring
•
•
•
•
NOMENCLATURE
Types of substituents
Symmetry I or III
Oxidation between rings
– Methylene -CH2– Methene -CH=
Heme
Fig.44.2
Page 836
Protoporphyrin III
prefix or suffi x
urocoproproto -porphyrinogen
-porphyrin
ring substituents
acetate, propionate
methyl, propionate
methyl, propionate, vinyl
---
between rings
--methylene
methene
Reactions for
Protoporphyrin IX
Fig. 44.3
Page 837
Step 1
Synthesis of d-amino levulinic acid
Fig. 44.4
837
Mitochondrial location
Rate limiting
Pyridoxal phosphate (decarboxylase)
Regulation of enzyme levels by iron
and protohemin
Step 2
Synthesis of porphobilinogen
Fig. 44.5
Page 838
Also called porphobilinogen synthase
Zinc-dependent
Site of lead toxicity
Further Reactions
• Step 3 Tetrapyrrole formation
– synthesis of hydroxymethylbilane
– synthesis of uroporphyrinogen III
• Step 4 Conversion to protoporphyrin III
– uro to copro
– copro to proto
– porphyrinogen to porphyrin
• Step 5 Protoheme synthesis
– insertion of ferrous iron
– site of lead toxicity
1
2
3
3
4
4
5
Heme Proteins
Protoheme (or heme) + globin ~ hemoglobin
Protohemin formation -- formation of superoxide
O2
protoheme
O2
protohemin (or hemin) contains Fe
Variations in heme
Fe ligands 4, 5, or 6
Ferrous or Ferric
Protoporphyrin III attachment to protein
3+
Heme b
Heme c
Heme a
Iron-IRE
Porphyrias
Treatment
Hematin (hemin hydroxide)
1
2
3
3
4
4
5
Heme
Degradation
Fig. 44.7
Page 839
Reactions
Fig. 44.8
Page 840
Heme oxygenase
Biliverdin reductase
Serum albumin
GSH S-transferase
Bilirubin UDP-glucuronyl transferase
Spleen Macrophages
Blood
Liver
Heme Degradation
• Features
• Reactions
• Jaundice
– hemolytic
– obstructive
– Neonate
kernicterus
– liver disease
– Gilbert’s disease
•Blood Proteins
–serum albumin
–haptoglobin
–hemopexin
Blood So Far
• Plasma
• Erythrocyte
– Hemoglobin
• Globin chains
• Protoporphyrin III
• Iron
Iron Balance
IRON METABOLISM
Fig. 44.6
Page 838
Iron Absorption
•
•
•
•
•
Low but regulated
Ferrous iron conversion needed
Heme iron by separate pathway
Reducing agents aid uptake-vitamin C
Factors in breast milk facilitate uptake
(lactoferrin)
Promoters and inhibitors of
non-heme iron absorption
• Promoters:
Ascorbic acid
Meat
Citric Acid
Some spices
-carotene
Alcohol
• Inhibitors:
Phytic acid
Polyphenols
Tannins
Calcium
Adapated from Paul Sharp Kings College UK
Duodenal iron transport
Fe3+
ferritin
DRA
Fe3+
Dcytb
Fe3+
Fe2+
DMT1
Fe2+
Tf
eeLIP
heme
HCP1
Fe3+
Fe2+
IREG1
Hp
HO
Plasma
Gut lumen
Adapated from Paul Sharp Kings College UK
Hepcidin Master Regulator
• Liver-produced antimicrobial peptide
• Lowers iron absorption by binding to
ferroportin, resulting in
internalization, and degradation
• Expression is COMPLEX and related
to liver iron mediated by TfR2 (Iron
induces).
• Expression increased by IL6
Iron transport
Steap3
Iron Storage
• Ferritin
• Serum ferritin
• Hemosiderin
Iron Utilization
• Heme synthesis
• Non-heme iron proteins
• Iron mobilization is dependent on
copper ferroxidases
Iron Mobilization
TfR and Ferritin
Posttranscription Regulation
Fig. 16.21 16.22
Page 290
Additional
IRE containing
mRNA transcripts
Include :
DMT1
ALA synthase
Ferroportin
Others
Iron Imbalance
• Excretion
• Deficiency
• Toxicity
– Hemochromatosis
– Seconday effects (genetic and
environmental)
Dcytb
Steap 2
DMT1
Ferritin
Ferroportin
Hephaestin
Heme Carrier Protein1
Heme Oxygenase
Transferrin
Hepcidin
HFE
(-microglobulin)
(transferrin receptor)
Nutritional Issues-Iron
• Deficiency
– Causes
– Diagnosis
– Consequences
• Supplementation
• Toxicity
Causes of Iron deficiency
• Pathological blood loss - hookworm
• Low bioavailability of iron in food
• Infection: more prevalent in developing
countries 58% of females in Asia vs 10% of
Western females are iron deficient
• Being female
• Pregnancy
•
Adapated from Paul Sharp Kings College UK
Consequences of Iron
Deficiency
•
•
•
•
•
Poor pregnancy outcomes
Increased perinatal morbidity
Defective psychomotor development
Impaired educational performance
Impaired work capacity
•
Adapated from Paul Sharp Kings College UK
Adapated from Paul Sharp Kings College UK
Micronutrients-Iron
• Dietary Recommended Intakes (DRI)
– RDAs are gender specific
– UL = 40 mg
Iron Absorption Adapts
70
60
50
40
30
Fe Absorption (%)
20
10
0
12
24
36
Weeks of Gestation
Barrett et al., 1994
Post Delivery
Micronutrients-Iron
• Food Sources
• Toxicity Concerns
• Supplementation Needed?
Young Women Iron
Zinc
Copper
EAR, mg
6.8
0.7
26
16
13
11
8
Age 14-18
16
% Below EAR
Age 19-30
15
% Below EAR
Supplements Necessary?