Term
| Name the two precursors of the porphyrin ring. |
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Definition
The synthesis of the complex porphyrin ring is achieved from two simple precursors,
succinyl CoA and
glycine. |
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Term
| Identify the rate controlling step in porphyrin synthesis? Name the enzyme that catalyzes this step and describe the reaction catalyzed. |
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Definition
The rate controlling step is the formation of ALA from succinyl CoA and glycine.
ALA synthase catalyzes this reaction.
Glycine forms a Schiff base with enzyme-bound pyridoxal phosphate (E-CHO). The resulting adduct reacts with
succinyl CoA to give enzyme-bound α-amino-β-ketoadipic acid, which is decarboxylated to give ALA. |
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Term
| Determine the number of molecules of 5-aminolevulinate required to make a pyrrole ring. |
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Definition
| Two molecules of ALA condense to form porphobilinogen (pyrrole ring) |
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Term
| Determine the number of molecules of succinyl CoA and glycine needed to make a pyrrole ring. |
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Definition
One molecule of succinyl CoA and one molecule of glycine form one ALA molecule.
Since two ALA molecules are needed to form the pyrrole ring (porphobilinogen), two molecules each of glycine and succinyl CoA are required. |
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Term
| State where (in the cell) the 5-aminolevulinate synthase reaction occurs. |
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Definition
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Term
| State where (in the cell) the porphobilinogen synthase reaction occurs. |
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Definition
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Term
| Describe the functions of uroporphyrinogen I synthase and uroporphyrinogen III cosynthase. |
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Definition
Uroporphyrinogen I synthase catalyzes the deamination of the porphobilinogen precursor and the head to tail condensation of four porphobilinogens to make a linear tetrapyrrole, hydroxymethylbilane.
Uroporphyrinogen III cosynthase catalyzes the closure of the porphyrinogen ring, with a simultaneous reversal of the final pyrrole. This product is called uroporphyrinogen III (AP-AP-AP-PA). |
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Term
| State the conditions under which uroporphyrinogen III will be formed. State the conditions under which uroporphyrinogen I will be formed. |
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Definition
Uroporphyrinogen III will be formed in normal conditions (uroporphyrinogen I synthase and uroporphyrinogen III cosynthase present)
Uroporphyrinogen I is formed in individuals with
a deficiency of uroporphyrinogen III cosynthase. Some of the hydroxymethylbilane spontaneously condense to uroporphyrinogen I (AP-AP-AP-AP), a compound with no known physiological function |
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Term
| Determine the number of pyrrole rings required to make protoporphyrin IX. |
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Definition
| 4 pyrrole rings (porphobilinogen) condense to form a porphyrin ring |
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Term
| Distinguish protoporphyrinogen IX from protoporphyrin IX. |
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Definition
| Protoporphyrinogen IX is converted by mitochondrial protoporphyrinogen oxidase to protoporphyrin IX. Four methene bridges are formed which link the four pyrrole rings. |
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Term
| List all the enzymes in the porphyrin synthetic pathway and indicate the subcellular location of each. |
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Definition
5 ALA synthase - mitochondria
ALA dehydratase - cytoplasm
uroporphyrinogen I synthase - cytoplasm
uropporphyrinogen III cosynthase - cytoplasm
uroporphyrinogen decarboxylase - cytoplasm
coproporphyrinogen oxidase - mitochondria
protoporphyrinogen oxidase - mitochondria |
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Term
| State the function of ferrochelatase. State which oxidation state of iron is incorporated into protoporphyrin IX. |
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Definition
| Ferrochelatase, an enzyme on the inner mitochondrial membrane, acts in the presence of reducing agents such as ascorbate or glutathione to insert Fe2+ into protoporphyrin IX, producing heme. |
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Term
| Describe the two mechanisms by which free heme regulates the formation of 5-aminolevulinate in liver cells and in erythrocyte precursors. |
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Definition
In its free form heme is oxidized to hemin.
Both heme and hemin are allosteric inhibitors of ALA synthase.
Hemin represses the rate of ribosomal ALA synthase as well |
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Term
| Distinguish between biliverdin and bilirubin. |
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Definition
Biliverdin is a linear tetrapyrrole with a green color formed when
heme complexes with an oxygenase system in the endoplasmic reticulum. A mixed function oxidase hydroxylates one ofthe methylidyne bridges, followed by a dioxygenase reaction in which the bridge is cleaved toliberate carbon monoxide and the iron atom, and form biliverdin.
Bilverdin is reduced by NADPH to form bilirubin which has a red-brown color |
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Term
| Distinguish between unconjugated (indirect) and conjugated (direct) bilirubin |
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Definition
Conjugated bilirubin is water-soluble and reacts directly when dyes are added to the blood specimen.
Uncongujated bilirubin is "free" and lipid soluble. It is called indirect because it does not react to the reagents until alcohol is added to the solution |
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Term
| Describe how indirect bilirubin is transported in plasma. State what purpose the UDP-bilirubin glucuronosyl transferase serves. Identify the major form of bilirubin in bile. |
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Definition
Indirect bilirubin is transprorted in the plasma bound to the plasma protein albumin
UDP-bilirubin glucuronosyl transferase catalyzes the addition of 2 UDP-glucuronic acids onto bilirubin (now it is conjugated)
Conjugated (or direct) bilirubin is the major form in the bile |
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Term
| Define jaundice. List the three types of jaundice. For each type of jaundice, determine which form of bilirubin (direct or indirect) will increase in plasma. |
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Definition
Jaundice is the condition in which blood contains excessive amounts of bilirubin
Prehepatic jaundice results from the greater than normal breakdown of erythrocytes beyond the capacity of the liver to form the diglucuronide. The resultant increase in the total plasma bilirubin concentration is mostly indirect bilirubin.
Hepatic jaundice results from damage or necrosis of the liver, as in hepatitis or cirrhosis. Increase in bilirubin in plasma is largely due to the indirect bilirubin
Posthepatic jaundice results when delivery of bilirubin to the intestinal tract is hampered caused by obstruction of the bile duct. Increase due to direct bilirubin |
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Term
| List the principal sites (tissue) of heme catabolism. |
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Definition
| The principal sites of heme catabolism are the liver, spleen, and bone marrow. |
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Term
| Define methemoglobin. Describe how its formation is minimized. |
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Definition
Methemoglobin is a nonfunctional hemoglobin in which the heme iron is oxidized to the ferric state (Fe 3+)
Methemoglobin formation may be minimized by removing superoxide and hydrogen peroxide, through the action of superoxide dismutase and glutathione peroxidase. |
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Term
| Describe the reaction which converts methemoglobin to hemoglobin. |
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Definition
| Methemoglobin is reduced by a NADH-cytochrome b5 reductase to form hemoglobin. |
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Term
| Explain why erythrocytes need an active pentose phosphate pathway. |
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Definition
NADPH is used to reduce glutathionine disulfide (GSSG) into reduced glutathionine (GSH)
The PP pathway produces NADPH |
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Term
| Describe the significance of reduced glutathione in erythrocytes. |
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Definition
Reduced glutathionine (GSH) is necessary to remove hydrogen peroxide.
Hydrogen peroxide is harmful to RBC's as it oxidizes hemoglobin to nonfunctional methemoglobin |
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Term
| Describe the term porphyria. List the major types of porphyria. For each type, list the enzyme deficiency. Describe how each of these porphyrias might be treated. |
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Definition
Porphyrias are diseases caused by an impairment of heme biosynthesis, with the accumulation of biosynthetic intermediates
Acute intermittent porphyria is deficiency in uroporphyrinogen I synthase and treatment is hemin and glucose
Erythropoietic porphyria is deficiency in uroporphyrinogen III cosynthase and treatment is ?
Erythropoietic protoporphyria is deficiency in ferrochetalase and treatment is ?
Porphyria cutanea tarda is deficiency in uroporphyrinogen decarboxylase and treatment is phlebotomy
Hereditary coproporphyria is deficiency in coproporphyrinogen oxidase and treatment is hemin
Variegate porphyria is deficiency in protoporphyrinogen oxidase and treatment is hemin |
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Term
| List the principal sites (tissue) of heme synthesis |
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Definition
~70 -80% occurs in erythrocyte precursors (remember RBC's lack mitochondria) in bone marrow
~15% occurs in the liver |
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Term
| Describe the effects of lead poisoning on porphyrin metabolism. List the principal enzymes affected. Describe how lead poisoning is treated. |
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Definition
Lead poisoning leads to increased levels of ALA (affects ALA dehydratase) and protoporphyrin IX (affects ferrochelatase).
It is treated by zinc administration and dimethylsuccinic acid |
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Term
| What is the function of haptoglobin in heme and iron metabolism? |
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Definition
| Haptoglobin is a carrier protein that binds to methemoglobin dimers after RBC destruction that occurs outside the spleen |
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Term
| What is the function of hemopexins in heme and iron metabolism? |
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Definition
Hemopexin is a carrier protein that binds to hemin after RBC destruction outside the spleen.
The hemopexin-hemin complex is then taken up by the liver. |
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Term
| What is the function of transferrin in heme and iron metabolism? |
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Definition
Transferrin is used to transport iron in the blood.
Transferrin mRNA contains an iron-response element. When iron is low, transferrin is high so that iron will be transported (instead of stored). |
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Term
| What is the function of ferritin in heme and iron metabolism? |
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Definition
Iron is stored in tissues in combination with proteins called ferritins
Ferritin mRNA contains an iron-response element so when iron is low, it is inhibited. The body doesn't want to store iron if iron is low as it needs to be transported and used. |
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Term
| What is the function of hemosiderin in heme and iron metabolism? |
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Definition
| Hemosiderin is a complex formed when the storage capacity of ferritins has been exceeded. The complex contains iron. |
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Term
| What is the function of ceruloplasmin in heme and iron metabolism? |
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Definition
| It is a ferroxidase that converts Fe2+ to Fe3+ in blood |
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Term
| What is the function of ferroportin in heme and iron metabolism? |
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Definition
| Ferroportin transports iron from the cells to the blood plasma |
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Term
| What is the function of hepcidin in heme and iron metabolism? |
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Definition
Hepcidin binds ferroportin to regulate egress of iron
from cells to plasma.
Hepcidin binding causes ferroportin to degrade which results in decreased iron being sent to the plasma |
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Term
| What is the function of ligandin in heme and iron synthesis? |
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Definition
| Ligandin is a protein that binds bilirubin in the liver cytosol |
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Term
List the characteristics of the disease, hemochromatosis. Describe how hemochromatosis is treated. Distinguish between primary and secondary
hemochromatosis |
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Definition
Hemochromatosis refers to a hereditary deficiency in control of iron absorption. It is characterized by hemosiderin deposits (amorphous iron deposition), particularly in pancreas, skin, heart muscle, and liver.
It is treated by plebotomy (draining blood from a vein).
Primary hemochromatosis is loss of regulation of absorption of iron is due to mutations.
Secondary hemochromatosis is caused by excessive iron accumulation due to repeated transfusions (due to thalassemias) |
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Term
| State where urobilins and stercobilins are formed |
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Definition
| In the bowels (intestine) |
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