Term
| Name the four classes of tetrapyrroles? |
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Definition
Heme Bilin Chlorophylls Corrins All are formed from 5-aminolevulinate and share a common biosynthetic pathway |
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Term
| What percentage of heme synthesis occurs in the liver? |
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Definition
15% All other heme synthesis occurs in erythrocyte precursors |
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Term
| Describe the initial formation of porphobilinogen |
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Definition
The first step is catalyzed by delta-aminolevulinate synthase (a mitochondrial enzyme), which uses glycine and succinyl CoA (the precursors) and requires pyridoxal 5 phosphate and Mg2+. Initially, Glycine forms Schiff Base with enzyme-bound pyridoxal phosphate and then reacts with Succinyl CoA to form alpha-amino-beta-ketoadipic acid, which is decarboxylated to form 5-aminolevulinic acid. In the cytosol, 2 molecules of aminolevulinate condense to form porphobilinogen, which is catalyzed by porphobilinogen synthase (aka ALA dehydratase). ALA dehydratase requires Zn2+. One molecule of 5-aminolevulinate forms a Schiff Base with ALA dehydratase. |
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Term
True/False Porphyrin synthesis reactions are thermodynamically favorable, but essentially reversible without an input on energy. |
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Definition
False...sorta They're energetically favorable and physiologically IRreversible without an input of energy. |
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Term
What effects do heme and hemin have on ALA synthase? |
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Definition
| Hemin is the oxidized form of heme. They both act as allosteric inhibitors of ALA synthase. |
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Term
| What effects do barbituates have on ALA synthase? |
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Definition
| Barbituates and 100 other drugs cause the induction of ALA synthase. They induce the synthesis of cytochrome P450 enzymes, which contain heme. The level of heme decreases, thus de-repressing the inhibition of ALA synthase. |
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Term
| What is the half-life of ALA synthase? |
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Definition
aka 5-aminolevulinate synthase has half-life = 60-70 minutes in rat liver |
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Term
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Definition
| Porphoryins in which the bridge between the pyrrole rings are in the reduced state |
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Term
| List the AP/PA sequences for each of the 4 possible uroporphyrins |
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Definition
Type I...AP-AP-AP-AP Type II...AP-PA-AP-PA Type III...AP-AP-AP-PA Type IV...AP-PA-PA-AP |
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Term
| Describe the synthesis of Uroporphorinogen III from porphobilinogen |
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Definition
4 molecules of porphobilinogen are deaminated and condensed to form hydroxymethylbilane (a liner tetrapyrrole molecule), which is catalyzed by uroporphorinogen I synthase. Uroporphorinogen III cosyntase catalyzes the closrue of the porphorinogen ring by reversing the last pyrrole ring to give AP-AP-AP-PA sequence (A=acetate group, P=proprionate group). THe closed ring is Uroporphorinogen III. In individuals with a deficiency of uroporphorinogen III cosynthase some hydroxymethylbilane spontaneously converts to form uroporphorinogen I (AP-AP-AP-AP), which has no known function. |
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Term
| Describe the synthesis of Heme from Uroporphorinogen III |
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Definition
Uroporphorinogen III is decarboxylated (the acetate groups are decarboxylated to methyl groups) by Uroporphorinogen decarboxylase to give coproporphorinogen III. Coproporphorinogen is shuttled into the mitochondria. Proprionic acid groups of rings A and B are decarboxylated to vinyl groups by coproporphorinogen oxidase to form protoporphorinogen IX. Protoporphorinogen IX is coverted to Protoporphyrin IX by Protoporphorinogen oxidase. Four methene bridges are formed to link the 4 pyrrole rings. Ferrochetalase acts (in the presence of reducing agents ascorbate or glutathione) by inserting a Fe2+ into protoporphyrin IX to form Heme. |
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Term
| What are the principal sites of heme catabolism? |
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Definition
| liver, spleen, bone marrow |
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Term
| Where does heme degradation generally begin? |
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Definition
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Term
True/False Porphyrin degradation begins with the reduction of heme to hemin with NADH |
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Definition
False Porphyrin degradation begins with the reduction of hemin to heme with NADPH |
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Term
| WHat is the major form of bilirubin excreted into bile? |
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Definition
Bilirubin Diglucoronide which is made by conjugation of bilirubin with UDP-glucoronate (which is made from UDP-glucose). Bilirubin diglucoronide is more soluble than the unconjuated bilirubin and can be excreted w/o crystallizing. |
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Term
| What are urobilinogens and stercobilinogens? |
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Definition
In the bowel, Bilirubin diglucoronide undergoes reduction reactions by microorganisms to form urobilinogens and stercobilinogens. Part of the urobilinogen is reabsorbed and secreted in the urine. Both compounds undergo reoxidation to form methylidyne bridges. The partially oxidized forms are called urobilins and stercobilins, which are responsible for the yellow and brown color of urine and feces |
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Term
| What are direct and indirect Van den Bergh reactions? |
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Definition
Direct: When conjugated bilirubin is expressed as direct bilirubin, which can be coupled readily with diazonium salts to for azo dyes. Indirect: unconjugated bilirubin is bound to albumin and will not be released until addition of ethanol. Reaction of diazonium can give total bilirubin (conjugated and unconjugated). AMt of conjugated can be calculating amt of azo dye in presence and absence of ethanol. |
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Term
| Describe Prehepatic Jaundice |
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Definition
Results from greater than normal break down of RBCs faster than liver can produce diglucoronide. This causes increase in bilirubin in the plasma (mainly indirect form). Sometimes found in infants born with Rh incompatibility. They must be exposed to blue light (400-500nm) to produce photobilirubin (which is more soluble than normal bilirubin). They are usually immature lack the enzyme needed to make diglucoronide. |
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Term
| Describe hepatic jaundice |
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Definition
Results from damage or necrosis of the liver (as in hepatitis or cirrhosis). Hepatic cells lose some ability to extract bilirubin from circulation and may lose function to make diglucoronide. Yellow color is due mainly to indirect bilirubin. Conjugated bilirubin may also enter the plasma due to membrane damage. |
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Term
| Describe Posthepatic Jaundice |
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Definition
aka Cholestatic Jaundice Results when delivery of bilirubin to the intestinal tract is hampered. Probably due to obstruction of the bile duct. Yellow skin color due to build up of direct bilirubin that would have been converted to urobilinogen and stercobilinogen. Also, decreased amt of urinary urobilinogen. Urine will be yellow to brown due to excretion of some bilirubin in the urine. |
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Term
| What is the significance of Z protein and ligandin in bilirubin metabolism? |
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Definition
Both Z protein and ligandin bind bilirubin the liver cytosol Z protein can also bind fatty acids Ligandin (aka Y protein) has lower capacity, but higher affinity for bilirubin than Z protein |
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Term
If hemoglobin is detroyed in areas other than the spleen, what carrier proteins are involved in the oxidized hemoglobin uptake? |
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Definition
Haptoglobins: Bind methemoglobin Hemopexins: bind hemin Albumin: binds hemin albumin's affinity for hemin is 1/60 that of hemopexin, but is present 50 times greater than hemopexin. Hemopexin deliveries hemin to the liver, while albumin gives hemin to hemopexin
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Term
| Acute intermittent Porphyria |
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Definition
enzyme: uroporphorinogen I synthase cmpds: porphobilinogen, 5 aminolevulinate treatment: hemin, glucose infusion
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Term
| Hereditary coproporphyria |
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Definition
coproporphorinogen oxidase cmpds: Coproporphorinogen III, 5 aminolevulinate, porphobilinogen treatments: hemin
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| Hemochromatosis secondary |
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