PORPHYRIN AND HEME METABOLISM

• Porphyrins metal and protein• Hemoproteins

– Heme– Hemoglobin

• Iron• Globin chains• Protoporphyrin III (IX)

PORPHYRINS

HC

HCNH

CH

CH

Pyrrole ring

• NOMENCLATURE• Types of substituents• Symmetry I or III• Oxidation between

rings– Methylene -CH2-– Methene -CH=

HemeFig.44.2Page 836

Protoporphyrin III

prefix or suffix ring substituents between rings uro- acetate, propionate -- copro- methyl, propionate -- proto- methyl, propionate, vinyl -porphyrinogen -- methylene -porphyrin -- methene

Reactions forProtoporphyrin IX

Fig. 44.3Page 837

Step 1Synthesis of -amino levulinic acidFig. 44.4837

Mitochondrial locationRate limitingPyridoxal phosphate (decarboxylase)Regulation of enzyme levels by iron and protohemin

Step 2Synthesis of porphobilinogenFig. 44.5Page 838

Also called porphobilinogen synthaseZinc-dependentSite 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

33

4

4

5

Heme ProteinsProtoheme (or heme) + globin ~ hemoglobin

O2 O2-

protoheme protohemin (or hemin) contains Fe3+

Protohemin formation -- formation of superoxide

Variations in hemeFe ligands 4, 5, or 6Ferrous or FerricProtoporphyrin III attachment to protein

Heme b Heme c Heme a

Iron-IRE

Porphyrias

TreatmentHematin (hemin hydroxide)

1

2

33

4

4

5

Heme Degradatio

nFig. 44.7Page 839

Reactions

Fig. 44.8Page 840

Heme oxygenaseBiliverdin reductaseSerum albuminGSH S-transferaseBilirubin UDP-glucuronyl transferase

Spleen MacrophagesBloodLiver

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 METABOLISMFig. 44.6Page 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 acidMeatCitric AcidSome spices-caroteneAlcohol

• Inhibitors:Phytic acidPolyphenolsTanninsCalcium

Adapated from Paul Sharp Kings College UK

LIP

e-

Fe3+

ferritin

e-

TfFe3+ Fe3+

Fe2+

HO

DMT1

Fe2+ HpIREG1

Fe2+

DcytbDRA

Fe3+

Gut lumen

Plasma

Duodenal iron transport

heme HCP1

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

Additional IRE containingmRNA transcriptsInclude :DMT1ALA synthaseFerroportinOthers

TfR and Ferritin Posttranscription RegulationFig. 16.21 16.22Page 290

Iron Imbalance

• Excretion • Deficiency• Toxicity

– Hemochromatosis– Seconday effects (genetic and

environmental)

Dcytb Steap 2DMT1Ferritin Ferroportin Hephaestin

Heme Carrier Protein1Heme Oxygenase

Transferrin HepcidinHFE(-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

0

10

20

30

40

50

60

70

12 36

Fe Absorption (%)

24 Post Delivery

Barrett et al., 1994

Weeks of Gestation

Micronutrients-Iron

• Food Sources• Toxicity Concerns• Supplementation Needed?

Young Women

Iron Zinc Copper

EAR, mg 8 6.8 0.7

Age 14-18

% Below EAR16 26 16

Age 19-30

% Below EAR15 13 11

Supplements Necessary?