Specialized products formed from amino acids

19-11-13 Dpt 4th semester

PORPHYRIN METABOLISM
Porphyrins are the cyclic compounds formed by four pyrole links through methenyl bridges metalloporphyrin In humans the most common metaloporphyrin is heme, consist of one ferous Fe+2 ion

Heme acts as prosthetic group for several molecules

Structural features are 1) Side chains: porphyrias vary due to nature of side chain attached to four pyrole rings Uroporphyrin contains acetate and propionate (A,P) side chains Coproporphyrin contains methyl and propionate groups (M,P) Protoporphyrin IX (heme) contains vinyl, methyl and propionate groups (V,M,P)

2) Distribution of the side chain: side chain of porphyrins can be arranged around tetrapyrrole nucleus in four ways designated I to IV Only type III porphyrin is physiologically important in humans which is asymmetric

Biosynthesis of heme
Major sites for the synthesis of heme are liver and erthrocytes. About 85% of heme is synthesized in erythoid tissue

The initial and last three steps of porphyrin synthesis occurs in mitochondria while the intermediate steps occur in cytosol

Formation of -aminolevulinic acid (ALA)

 More the porphyrin production more will be the heme (hemin) which decreases ALAS1 Drug administration will increase ALAS1 activity thus increasing heme consumption so heme would become lower which will increase ALAS1

Formation of porphobilinogen by ALA-dehydratase

So
Porpho-uro-copro-proto-protoporphyrin IX

 Porphyrias result due to deficiency of any enzyme in the heme synthesis pathway Causes increased accumulation & excretion of porphyrins Purple pigment appeared in urine of patients
porphyrin

hepatic

erthyropoietic

acute

chronic

 individuals with enzyme defects prior to the tetra pyrrol formation will show abdominal and neurophysiatric signs while Individuals showing enzyme defects leading to pyrrole formation shows photosensitivity

Hepatic porphyrias

chronic

acute

Deficiency of uroporphyrinogen decarboxylase

iron overload, photosensitivity, hepatitis B,C, HIV infections

ALA dehydratase gastointestinal, neurophysiatric attacks

 Erthyroid porphyria: deficiency of Ferrochelatase VARIEGATE PORPHYRIA deficiency in Protoporphyrinogen oxidase

HEREDITARY COPROPORPHYRIA deficiency in Coproporphyrinogen oxidase

Treatment of porphyrias
Symptoms of porphyrias can be diminished by ingestion of glucose and hemin which decreases the synthesis of ALAS1 Sunlight avoidance and -carotene are also helpful for treatment

Heme degradation

 Solubility in hepatocytes increased by addition of two molecules of glucuronic acid (conjugation) Reaction catalysed by bilirubin glucuronyl transferase Deficiency of this enzyme results in CriglerNajjar I & Gilbert syndrome

Jaundice is characterized by excess accumulation of bilirubin in blood Symptoms are yellowing of nail beds, sclera and skin colour Types of jaundice a) hemolytic b) hepatocellular C) obstructive In new borns hepatic bilirubin glucoronyl transfease is low at birth

Other nitrogen containing compounds

Catecholamines: epinephrine, nor epinephrine,dopamine collectively called neurotransmitters

Histamine allergic and inflammatory

reactions, gastric acid secretion, and possibly neurotransmission

Serotonin has multiple

physiologic roles, including pain perception, regulation of sleep,appetite, temperature, blood pressure

Creatine
Creatine is a high energy reserve, rapidly provides ADP to maintain ATP during muscle contraction.

Melanin synthesized from tyrosine in the epidermiis Its function is to protect cells from the harmful effects of sunlight Defect in Cu containing tyrosinase causes albinism