Hemoglobin and Porphyria Cutanea Tarda

AMP and GMP can be converted to ATP and GTP through phosphorylation by kinases

IMP is a precursor for pyridine synthesis and is rapidly converted in nucleotide synthesis

Nucleoside monophosphate/diphosphate kinases play a role in phosphorylation of AMP to ADP and GMP to GDP

Adenylate Kinase and Guanylate Kinase are the kinases responsible for the phosphorylation of AMP and GMP respectively

Regulation of purine biosynthesis is controlled by the concentrations of both adenine and guanine nucleotides, which affects the production of IMP

Purine nucleotides are degraded to uric acid and excreted in the urine

Hypoxanthine, a base in purine nucleotides, is oxidized to uric acid by xanthine oxidase, but can be utilized by the salvage pathway

The salvage pathway allows the body to reuse hypoxanthine and guanine by forming IMP and GMP

The inability to salvage hypoxanthine and guanine due to a deficiency in HGPRT results in Lesch-Nyhan Syndrome, which is characterized by neurological abnormalities and excessive uric acid production

Pyrophin's and Nucleotide Metabolism can be treated with Allopurinol, an inhibitor of xanthine oxidase, and Colchicine for acute arthritic attacks in gout

Adenosine Deaminase is an enzyme of purine nucleotide degradation and an autosomal recessive deficiency of this enzyme results in severe combined immunodeficiency (SCID)

Pyrimidine synthesis regulation involves the synthesis of carbamoyl phosphate and its role in forming the orotate ring

UMP is decarboxylated to form uridine, which is a precursor of all pyrimidine nucleotides

UMP is used to form UTP through similar synthesis as purine triphosphates

Methylenetetrahydrofolate is involved in the formation of Thymidylate, which is essential for DNA synthesis

Uridine monophosphate is the precursor of all pyrimidine nucleotides

Deoxyribonucleotides of Adenine, Guanine, and Cytosine are synthesized from ribonucleotides by reduction of 2-hydroxyl by ribonucleotide reductase.

Hepatic and Erythropoietic Porphyria Cutanea Tarda: occurs on sun-exposed hands, characterized by photosensitivity due to complement/mast cell activation

Hemoglobin (Hb): a globular protein, tetramer made up of 2 alpha and 2 beta polypeptide chains

Each polypeptide chain contains one heme, which holds Fe2+ at its core

Heme: Fe2+ bound to nitrogens of porphyrin ring and histidine residue of the polypeptide chain; can form bonds with O2

Quaternary Hb structure: Deoxy vs Oxy Hb

• Deoxy Hb (T-State): tense, salt bridges between alpha and beta dimers
• Oxy Hb (R-State): relaxed, weaker interactions between heterodimers
• Both states have a 2,3 bisphosphoglycerate (2,3 BPG) cavity

RBC concentration equals Hb concentration

Myoglobin: oxygen storage protein in the cytosol of skeletal, cardiac, and smooth muscle cells

• Binds oxygen released by hemoglobin in tissue capillaries and diffused to tissue
• Stored oxygen is available to mitochondria

Hemoglobin Oxygen Dissociation Curve: Oxygen saturation vs PO2, sigmoid curve, displays how effectively Hb releases O2 in tissues

• Increase in affinity: multiple oxygen molecules bind to different polypeptide chains
• Allosteric effectors: shift oxygen binding curve right or left

Carbon Monoxide (CO): greater affinity for Hb than O2, binds to the iron of heme

• Smokers have higher levels of Carboxyhemoglobin (COHb)
• CO binding changes Hb conformation from deoxy to oxy

Conditions: Hb saturation varies with PO2

• Hb is 50% saturated when PO2 is 26 mmHg
• Hb is 95% saturated when PO2 is 100 mmHg
• Hb is 75% saturated in resting muscle capillaries when PO2 is 45 mmHg

Fetal Hemoglobin (HbF): higher affinity for O2, allows for exchange between mother and fetus, binds to 2,3 BPG less efficiently

• After birth, gamma gene is turned off, and beta gene is turned on
• Most Hb is HbA1 (adult form) after 6 months

Hemoglobinopathies: genetic disorders affecting Hb

• Sickle cell: structurally abnormal Hb, HbS
• Sickle cell disease: homozygous, two copies of mutant beta gene
• Sickle cell trait: heterozygous, one copy of mutant beta gene
• Thalassemias: insufficient amount of Hb due to imbalance in globin chain synthesis
• Anemia: caused by abnormal or non-functioning globin genes
• Ferric Heme: methemoglobin (HbM) causes cyanosis and hypoxia
• Abnormal globin synthesis: thalassemia causes anemia

Cytochrome P450: liver detoxification and excretion of drugs/foreign substances

• Some drugs induce enzymes of hepatic-metabolizing systems containing P450 heme
• Pyrophin’s and Nucleotide Metabolism: RBCs are turned over after 4 months
• First step: Heme degradation to bilirubin within macrophages of the reticuloendothelial system
• Second step: Conjugated bilirubin transported to the liver, bile ducts, and excreted
• Third step: Intestines convert some conjugated bilirubin to urobilinogen, excreted through urine
• Fourth step: Kidneys convert some urobilinogen to urobilin, excreted through urine
• Hyperbilirubinemia: normal serum bilirubin is less than 0.8 mg/dl, most is unconjugated
• In hyperbilirubinemia, the level is greater than 2 mg/dl.

Hepatic and Erythropoietic Porphyria Cutanea Tarda: occurs on sun-exposed hands, characterized by photosensitivity due to complement/mast cell activation

Hemoglobin (Hb): a globular protein, tetramer made up of 2 alpha and 2 beta polypeptide chains

Each polypeptide chain contains one heme, which holds Fe2+ at its core

Heme: Fe2+ bound to nitrogens of porphyrin ring and histidine residue of the polypeptide chain; can form bonds with O2

Quaternary Hb structure: Deoxy vs Oxy Hb

• Deoxy Hb (T-State): tense, salt bridges between alpha and beta dimers
• Oxy Hb (R-State): relaxed, weaker interactions between heterodimers
• Both states have a 2,3 bisphosphoglycerate (2,3 BPG) cavity

RBC concentration equals Hb concentration

Myoglobin: oxygen storage protein in the cytosol of skeletal, cardiac, and smooth muscle cells

• Binds oxygen released by hemoglobin in tissue capillaries and diffused to tissue
• Stored oxygen is available to mitochondria

Hemoglobin Oxygen Dissociation Curve: Oxygen saturation vs PO2, sigmoid curve, displays how effectively Hb releases O2 in tissues

• Increase in affinity: multiple oxygen molecules bind to different polypeptide chains
• Allosteric effectors: shift oxygen binding curve right or left

Carbon Monoxide (CO): greater affinity for Hb than O2, binds to the iron of heme

• Smokers have higher levels of Carboxyhemoglobin (COHb)
• CO binding changes Hb conformation from deoxy to oxy

Conditions: Hb saturation varies with PO2

• Hb is 50% saturated when PO2 is 26 mmHg
• Hb is 95% saturated when PO2 is 100 mmHg
• Hb is 75% saturated in resting muscle capillaries when PO2 is 45 mmHg

Fetal Hemoglobin (HbF): higher affinity for O2, allows for exchange between mother and fetus, binds to 2,3 BPG less efficiently

• After birth, gamma gene is turned off, and beta gene is turned on
• Most Hb is HbA1 (adult form) after 6 months

Hemoglobinopathies: genetic disorders affecting Hb

• Sickle cell: structurally abnormal Hb, HbS
• Sickle cell disease: homozygous, two copies of mutant beta gene
• Sickle cell trait: heterozygous, one copy of mutant beta gene
• Thalassemias: insufficient amount of Hb due to imbalance in globin chain synthesis
• Anemia: caused by abnormal or non-functioning globin genes
• Ferric Heme: methemoglobin (HbM) causes cyanosis and hypoxia
• Abnormal globin synthesis: thalassemia causes anemia

Cytochrome P450: liver detoxification and excretion of drugs/foreign substances

• Some drugs induce enzymes of hepatic-metabolizing systems containing P450 heme
• Pyrophin’s and Nucleotide Metabolism: RBCs are turned over after 4 months
• First step: Heme degradation to bilirubin within macrophages of the reticuloendothelial system
• Second step: Conjugated bilirubin transported to the liver, bile ducts, and excreted
• Third step: Intestines convert some conjugated bilirubin to urobilinogen, excreted through urine
• Fourth step: Kidneys convert some urobilinogen to urobilin, excreted through urine
• Hyperbilirubinemia: normal serum bilirubin is less than 0.8 mg/dl, most is unconjugated
• In hyperbilirubinemia, the level is greater than 2 mg/dl.

AMP and GMP can be converted to ATP and GTP through phosphorylation by kinases

IMP is a precursor for pyridine synthesis and is rapidly converted in nucleotide synthesis

Nucleoside monophosphate/diphosphate kinases play a role in phosphorylation of AMP to ADP and GMP to GDP

Adenylate Kinase and Guanylate Kinase are the kinases responsible for the phosphorylation of AMP and GMP respectively

Regulation of purine biosynthesis is controlled by the concentrations of both adenine and guanine nucleotides, which affects the production of IMP

Purine nucleotides are degraded to uric acid and excreted in the urine

Hypoxanthine, a base in purine nucleotides, is oxidized to uric acid by xanthine oxidase, but can be utilized by the salvage pathway

The salvage pathway allows the body to reuse hypoxanthine and guanine by forming IMP and GMP

The inability to salvage hypoxanthine and guanine due to a deficiency in HGPRT results in Lesch-Nyhan Syndrome, which is characterized by neurological abnormalities and excessive uric acid production

Pyrophin's and Nucleotide Metabolism can be treated with Allopurinol, an inhibitor of xanthine oxidase, and Colchicine for acute arthritic attacks in gout

Adenosine Deaminase is an enzyme of purine nucleotide degradation and an autosomal recessive deficiency of this enzyme results in severe combined immunodeficiency (SCID)

Pyrimidine synthesis regulation involves the synthesis of carbamoyl phosphate and its role in forming the orotate ring

UMP is decarboxylated to form uridine, which is a precursor of all pyrimidine nucleotides

UMP is used to form UTP through similar synthesis as purine triphosphates

Methylenetetrahydrofolate is involved in the formation of Thymidylate, which is essential for DNA synthesis

Uridine monophosphate is the precursor of all pyrimidine nucleotides

Deoxyribonucleotides of Adenine, Guanine, and Cytosine are synthesized from ribonucleotides by reduction of 2-hydroxyl by ribonucleotide reductase.