The porphyrins are heterocyclic ring structures that include ___ pyrrole rings joined together through carbon (methenyl) bridges. The most abundant porphyrins in nature are found in hemoglobin and the chlorophylls. In the center of porphyrins a metal atom is chelated to the ___ atoms of the pyrrole units. In heme and related porphyrins this metal atom is ___. In chlorophyll the metal atom is magnesium.
Porphyrin Synthesis: step 1
- glycine + succinyl CoA -> 5-aminolevulinate (ALA)
- rate limiting step
- catalyzed by ALA synthase (5-aminolevulinate synthase, δ-aminolevulinate synthase)
- inhibited by heme (neg feedback)
- linear structure
Porphyrin Synthesis: step 2
- two 5-aminolevulinate -> monopyrrole, porphobilinogen
- still linear; in later steps cyclization, condense, eventually forms heme
- catalyzed by ALA dehydratase (Porphobilinogen Synthase)
- inhibited by lead
- the last step is catalyzed by Ferrochelatase, which is also inhibited by lead
The first reaction and the last three reactions of heme synthesis occur in _______ with the other four reactions being in the _____.
Regulation of hemoglobin synthesis involves balancing of ______ and ______ synthesis via accumulation of ____, or ______, its spontaneously oxidized free form, which inhibits ________ (synthesis and functioning), and activates _______.
- ALA synthase
- the synthesis of globin peptide
Hemin inhibits ALA synthase both in the _______ synthesizing hemoglobin and in other cells in which _______ are made.
- primitive red blood cell
- the cytochromes and other heme proteins
- heme synthesis disorders
- other than lead poisoning and acute intermittent porphyria (affect the earliest steps in heme synthesis, no porphyrin structure produced yet), all show light sensitivity, due to the accumulation of porphyrin
- skin, abdominal pain, neuropsychiatric
Porphyria Cutanea Tarda
The most common porphyria
deficiency in Ferrochelatase
Degradation of red cell
- heme -> billirubin, heme oxidase, by macrophages
- apoprotein -> AAs
- heme is opened and subject to oxidation to yield biliverdin, iron and carbon monoxide
- iron is reutilized
- Biliverdin: reduced to bilirubin by biliverdin reductase
- Bilirubin: transferred to liver as bilirubin-albumin complex. made more soluble in liver by conjugation with glucuronic acid from UDP-glucuronic acid, catalyzed by glucuronate transferase.
- increased breakdown of hemoglobin
- causes increase in billirubin, hyperbilirubinemia
the clinical syndrome associated with elevated serum level of bilirubin (>1 mg/dl)
Oxygen transport is mediated by two heme proteins:
- myoglobin: muscle; a single polypeptide chain
- hemoglobin: red blood cells; four polyeptide chains
________ is the major Hb type in adults and has _______ chains. Each subunit has a _______ containing ________.
- Hemoglobin A
- two alpha and two beta
- hydrophobic pocket
- the heme unit
oxygen affinity of heme proteins
- greater affinity for oxygen
- rectangular hyperbola oxygen binding curve
- sigmoidal oxygen binding curve
- cooperativity exists in the binding of the four oxygen molecules.
- The binding of oxygen to hemoglobin is decreased by a decrease in pH (Bohr effect) and by an increase in the level of 2,3-bisphosphoglycerate.
the iron in hemoglobin must be maintained in the ______ state for the transport of oxygen.
Oxidation of the iron of hemoglobin (Fe2+ -> Fe3+) forms _______, which can be caused by _____ and some drugs.
The reverse of this process can be achieved by several _________ enzymes.
- NADH or NADPH-linked
The cooperativity in binding the four O2 molecules involves two conformational states:
- T (tense) and R (relaxed).
- Binding of oxygen to one subunits favors conversion from T to R state
- R state has a higher affinity for oxygen.
lower pH results in
- lower O2 affinity
- right shift
- greater pO2 needed to reach the same level of saturation
increase 2,3-BPG results in
- right shift
- happens in adaptation to high altitudes
Glucosylation of hemoglobin occurs in ______ and may serve to measure _____.
- diabetes mellitus
- chronic elevation of blood glucose levels
One of the most important hemoglobinopathies of genetic origin is ________: occurs when the individual is _______ for a point mutation of substitution of ____ for ____ in the ___ subunits; causing hemolytic anemia, painful crises and poor circulation.
- sickle cell anemia
The thalassemias are a group of hereditary diseases in which there are defects in the synthesis of _________.
either the alpha or the beta chains
Both thalassemias and sickle cell anemia are found in __________.
- individuals of genetic origins from areas historically affected by malaria
- both have certain resistance to it
Carbon monoxide binds to hemoglobin _____ than oxygen and it ______ oxygen release.
Vitamins are ____ compounds ________ in small amounts. They are conveniently classed as ________.
- required in the diet
- fat soluble (A, D, E and K) or water soluble (C and the B complex)
Function: _____ is a precursor for _____ that is used in the ______ and for ________ that is required for maintenance of ______ cells. In the visual cycle, ___ binds the ____. Light causes the conversion to the ____ isomer which is ______ bound to opsin.
_____ can be metabolized to form vit A
Oxidation of retinal to retinoic acid is ______ and functions as _______.
- visual cycle
- retinoic acid
- 11-cis isomer of retinal
- only weakly
- a ligand for nuclear receptors that function in the regulation of gene transcription
Function: Thiamine is converted to thiamine pyrophosphate which is a cofactor for _______ of alpha-keto acids and for _______ (pyruvate decarboxylases and AKG decarboxylases)
Effect of Deficiency: ______ syndrome. _____, cardiac pathology, edema
- oxidative decarboxylation
- Beriberi (polished rice) and Wernicke Korsakoff
Function: precursor for the coenzymes, _____.
Effect of Deficiency: atrophy of ______, ______
- FMN and FAD
- filliform papillae
- angular cheilosis
NIACIN (NICOTINIC ACID)
Function: As nicotinic acid or ____ it is a precursor for the coenzymes _______.
Some niacin can be synthesized from _____.
Effect of Deficiency: ______
- NAD and NADP
- Pellagra (dermatitis, diarrhea, dementia and if severe, death)
PYRIDOXINE (VITAMIN B6)
Function: Pyridoxine (pyridoxol) is a precursor of _______ which is a coenzyme for enzymes catalyzing ________ and for ________.
- pyridoxal phosphate
- transamination, deamination, decarboxylation
- glycogen phosphorylase
Function: Biotin acts as a coenzyme in _________ reactions in covalent linkage to ____ side chains of enzymes.
Strongly bound by _____ in raw eggs.
Deficiency is ___
Function: Pantothenic acid is a precursor of _____. This structure forms part of ______.
Function: Folic acid is a precursor for ______ that is used as a carrier of _____ at different levels of ____. needed for purine, thymine synthesis, amino acid metabolism.
Effect of Deficiency: _______, ________.
- tetrahydrofolate THF
- one carbon units
- Megaloblastic anemia
- GI disturbances
VITAMIN B12 (______)
Function: precursors of cofactors used for: I. conversion of ________; II. conversion of ______.
Vitamin B12 is absorbed from the ____ as a complex with ______ which is produced by the gastric mucosa.
Effect of Deficiency: _______ and _______.
- methylmalonyl CoA to succinyl CoA
- homocysteine to methionine
- intrinsic factor
- Pernicious anemia (not correctable by iron administration)
- degeneration of spinal cord neurons
VITAMIN C (______)
Function: a water soluble _____; promotes the hydroxylation of proline residues of ___. Ascorbic acid is also required in the synthesis of ______.
Effect of Deficiency: ____ (_______).
- ASCORBIC ACID
- carnitine, dopamine and bile acids
- hemorrhage, impaired wound healing and bone formation
Function: Regulation of _____ levels through actions on ________. Vitamin D3 (cholecalciferol) requires conversion to ______ vitamin D3 to form the active compound.
Effect of Deficiency: ______, _______
- intestine, kidney and bone
VITAMIN E (________)
Function: a lipid-soluble ______ and helps to prevent ______.
- lipid damage
Function: coenzyme for the carboxylation of glutamic acid side chains (gamma carboxylation, forms two carboxyls, good for binding calcium ions) of some ________.
Effect of Deficiency: rare; can be associated with ______.
- blood clotting factors (prothrombin, factors VII, IX and X)
- prolonged blood clotting times