PORPHYRINSHEME SYNTHESIS AND DEGRADATION

Heme

PORPHYRINS Cyclic compounds that bind metal ions Chlorphyll (Mg2+)

Central to solar energy utilization Heme (Fe2+)

Most prevalent metalloporphyrin in humans Central to oxygen sensing and utilization

Cobalamin (Cobalt)

PORPHYRINS

HC

HCNH

CH

CH

Pyrrole ring

Porphyrin: Cyclic molecule formed by

linkage of four pyrrole rings through methenyl

bridges

PORPHYRIN SIDE CHAINS

M = Methyl (-CH3)

V = Vinyl (-CH=CH2)

P = Propionyl (-CH2-CH2-COO-)

A = Acetyl (-CH2-COO-)

HEME

One ferrous (Fe2+) atom in the center of the tetrapyrrole ring of Protoporphyrin IX

Prosthetic group forHemoglobin and MyoglobinThe CytochromesCatalase and Tryptophan pyrrolaseNitric Oxide Synthase

Turnover of Hemeproteins (Hemoglobin, etc) is coordinated with synthesis and degradation of porphyrins

Bound iron is recycled

Heme

Protoporphyrin III

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

BIOSYNTHESIS OF HEME

Synthesized in every human cell Liver (15%): Bone Marrow (80%)

COOH

CH2

CH2

COSCoACH2 NH2

COOH

SUCCINYL CoA

GLYCINE

All Carbon and Nitrogen atoms provided by 2 building blocks:

COOH

CH2

CH2

COSCoACH2 NH2

COOH

SUCCINYL CoA

GLYCINE isDecarboxylated

IN MITOCHONDRIA

AMINOLEVULINIC ACID SYNTHASE

- CO2

COOH

CH2

CH2

C=OCH2

NH2

Condense to form: AMINOLEVULINIC ACID (ALA)

MOVES OUT OF THE MITOCHONDRION

COOH

CH2

CH2

C=OCH2

NH2

COOH

CH2

CH2

C=OCH2

NH2

2 Molecules dehydrated byALA DEHYDRATASE

-2 H2O

COOH

CH2

CH2

CC

NH

COOH

CH2

C

CCH2

NH2

To form Porphobilinogen (PBG)

COOH

CH2

CH2

NH

COOH

CH2

CH2

NH2

Porphobilinogen (PBG)

AcetateCH2COO-

PropionateCH2CH2COO-

Porphobilinogen (PBG)

NH

CH2

NH2

A P

NH

CH 2

NH 2

A

PN

H

CH

2

NH2

A

P

NH

CH2

NH2

A

P

NH

CH2

NH2

A

P

HYDROXYMETHYLBILANE SYNTHASE& UROPORPHYRINOGEN III SYNTHASE

Four PBG molecules condense Ring closure Isomerization

NH

NH HN

HN

A B

CD

A

A

P

A

P

P

P

A

Uroporphyrinogen III

NH

NH HN

HNHOOC-H2C-

HOOC-H2C-

-CH2-CH2-COOH

-CH2-COOH

CH2

CH2

COOH

CH2

CH2

COOH

COOHCH2

CH2

COOHCH2

Uroporphyrinogen III

SERIES OF DECARBOXYLATIONS & OXIDATIONS

Porphyrinogens: Chemically reducedColorless intermediates

Porphyrins: Intensely coloredFluorescent

Uroporphyrinogen III Coproporphyrinogen IIIMoves back into Mitochondrion Protoporphyrinogen IX Protoporphyrin IX

NH

N HN

NH3C-

H3C-

-CH=CH2

-CH3

CH2

CH2

COOH

CH2

CH2

COOH

CH3

Protoporphyrin IX

CH=CH2

HEMEFe2+ chelated by Protoporphyrin IX

Assisted by Ferrochelatase

CH3-

REACTIONS FORPROTOPORPHYRIN IX

REGULATION OF HEME SYNTHESIS

AMINOLEVULINIC ACID SYNTHASE Two tissue-specific isozymes Coded on separate genes In Liver, heme represses synthesis and

activity of ALAS Heme can be used for treatment of acute

porphyric attack In RBC heme synthesis regulation is more

complex Coordinated with globin synthesis

COOH

CH2

CH2

COSCoACH2 NH2

COOH

SUCCINYL CoA

GLYCINE

IN MITOCHONDRIA

AMINOLEVULINIC ACID SYNTHASERATE-CONTROLLING STEP IN

HEPATIC HEME SYNTHESIS

COOH

CH2

CH2

C=OCH2

NH2

ALA

BonkovskyASH Education BookDecember 2005

DISORDERS OF HEME SYNTHESIS

Acquired: Lead poisoning

Congenital: Porphyrias

Deficiency of heme has far-reaching effects (hemoglobin, cytochromes, etc.)

LEAD TOXICITY

Symptoms Irritibility Poor appetite Lethargy Abdominal pain (with or Sleeplessness without vomiting) Headaches Constipation

Pathophysoiology Binds to any compound with a sulfhydryl group Inhibits multiple enzyme reactions including those involved in heme biosynthesis (ALA dehydratase & ferrochelatase)

COOH

CH2

CH2

C=OCH2

NH2

COOH

CH2

CH2

C=OCH2

NH2

-2 H2O

ALA moves out of the mitochondrion

ALA DEHYDRATASEInhibited by Heavy Metal: LEAD POISONING

PBG

NH

CH2

NH2

A P

Lead Poisoning

Lead PoisoningALAD and FerrochelataseAre particularly sensitive

to Lead inhibition

Lead Poisoning

Fe + PPIX

Ferrochelatase

Heme

PORPHYRIAS A group of rare disorders caused by deficiencies of enzymes of the heme biosynthetic pathway

The majority of the porphyrias are inherited in a autosomal dominant fashion - thus, affected individuals have 50% normal levels of the enzymes, and can still synthesize some heme

Affected individuals have an accumulation of heme precursors (porphyrins), which are toxic at high concentrations

Attacks of the disease are triggered by certain drugs, chemicals, and foods, and also by exposure to sun

Treatment involves administration of hemin, which provides negative feedback for the heme biosynthetic pathway, and therefore, prevents accumulation of heme precursors

Scriver et al., The Metabolic & Molecular Basis of Inherited Disease, 8th edition, 2001.

ACUTE INTERMITTENT PORPHYRIA

Hepatic, autosomal dominant

Caused by a deficiency in porphobilinogen deaminase, which is involved in the conversion of porphobilinogen (PBG) to uroporphyrinogen III

PBG, uroprophryin, and 5-ALA accumulate in the plasma and the urine

Patients have neuropyschiatric symptoms and abdominal pain (neurovisceral)

PORPHYRIA CUTANEA TARDAMost common porphyria

Hepatic, autosomal dominant

Disease is caused by a deficiency in uroporphyrinogen decarboxylase, which is involved in the conversion of uroporphyrinogen III to coproporphyrinogen III

Uroporphyrinogen accumulates in urine

Patients are photosensitive (cutaneous photosensitivity)Accumulation of porphyrinogens results in their conversion to porphyrins by light

Porphyrins react with molecular oxygen to form oxygen radicals

Oxygen radicals can cause severe damage to the skin

HEME DEGRADATION

REACTIONSFIG. 44.8

Heme oxygenaseBiliverdin reductaseSerum albuminBilirubin 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