6th Unit / Ch 21 Conversion of Amino Acids to Specialized Products Flashcards
Heme Structure and Synthesis 21 1.1
Based on the figure, to what series of the porphyrins (cyclic tetrapyrroles) does
heme belong?
What are some examples of heme-containing proteins?
In heme, the side chains are asymmetrically distributed on one of the pyrrole rings, placing heme in the III series of the porphyrins.
[Note: IX reflects an older naming system and is equivalent to III.]
Hb, Mb, CYP monooxygenases, NOS, and catalase, are examples of proteins that contain heme, a metalloporphyrin that functions as a prosthetic group.
Heme Structure and Synthesis 21 1.2
What are the major sites of heme synthesis in the body?
What subcellular sites
are involved?
What is the rate-limiting, committed reaction?
The liver and RBC-producing cells of the marrow are the major sites of heme synthesis, with more than 85% occurring in the marrow. Enzymes of the mitochondria and the cytosol are required.
The rate-limiting, committed step is the mitochondrial synthesis of ALA from Gly and succinyl CoA by PLP-requiring isozymes, ALAS1 and ALAS2 .
Heme Structure and Synthesis 21 1.3
Why might use of statins, cholesterol-lowering drugs metabolized by the hepatic
CYP system, cause an increase in heme synthesis in the liver?
ALAS1 (the ubiquitous isozyme) is regulated by heme (shown), which represses gene transcription, increases mRNA degradation, and decreases enzyme import into mitochondria. Use of heme in the synthesis of the hepatic CYP enzymes needed to metabolize the statins prevents heme from accumulating. This favors activation of ALAS1 and, consequently, heme synthesis in the liver.
[ Note: ALAS2 (the isozyme specific to erythroid tissue) is regulated by iron: as iron ↑, synthesis of ALAS2 ↑.
Heme Synthesis 21 2.1
What metal inhibits the reaction shown?
Are any other reactions of heme synthesis
similarly affected?
Lead inhibits the ALA dehydratase - catalyzed condensation of two ALA to porphobilinogen a pyrrole. Mitochondrial ferrochelatase, which inserts Fe2+ into protoporphyrin IX in the final step of heme synthesis, is also inhibited.
Consequently, lead poisoning causes microcytic anemia .
Heme Synthesis 21 2.2
How is protoporphyrin IX synthesized from porphobilinogen?
Four porphobilinogens are condensed in the cytosol to hydroxymethylbilane (a linear
tetrapyrrole), which is enzymatically cyclized and isomerized to uroporphyrinogen III, which, in turn, undergoes UROD -catalyzed decarboxylation of all its acetate groups (to methyl) to produce coproporphyrinogen III. This product moves into the mitochondrion and undergoes
decarboxylation and oxidation of two propionyl groups (to vinyl) to form protoporphyrinogen IX, which gets oxidized to protoporphyrin IX. Insertion of Fe2+ yields heme.
[Note: Deficiency of uroporphyrinogen III synthase results in overproduction of the I series porphyrins.]
Heme Synthesis 21 2.3
What are the porphyrias , and how are they classified?
Which is most common?
Porphyrias are rare, inherited (AD, primarily) or acquired (e.g., lead poisoning ) enzymatic deficiencies in heme synthesis in which porphyrins (or their precursors) accumulate and are excreted. They are classified as hepatic or erythropoietic. Hepatic forms are further classified as acute or chronic. PCT, a chronic porphyria caused by UROD deficiency, is the most common. Patients are photosensitive due to the light-induced oxidation of porphyrinogens to porphyrins.
Cutaneous symptoms (shown) and urine that turns reddish-brown are seen.
[Note: In the hepatic porphyrias ↓ heme synthesis ↑ ALAS1 activity, thereby allowing synthesis of intermediates prior to the defective enzyme. Their accumulation causes the clinical manifestations of the porphyrias.]
Heme Degradation 21 3.1
What is the primary source of the heme that is degraded by macrophages of the RES, as
shown? What enzyme catalyzes the initial step of degradation?
About 85% of the heme degraded by RES macrophages comes from the Hb of senescent RBCs, and the rest comes from proteins other than Hb. Microsomal heme oxygenase uses O2 and NADPH to convert cyclic heme to linear biliverdin. CO, Fe2+ , and NADP+ are also produced. Biliverdin is reduced to bilirubin by NADPH-requiring biliverdin reductase, enters into the blood, and is bound by albumin for transport to the liver.
Heme Degradation 21 3.2
What is the function of bilirubin UGT?
What is the fate of its product?
Bilirubin UGT is the hepatic microsomal enzyme that converts bilirubin to bilirubin diglucuronide (thereby increasing its solubility) through the addition of two molecules of glucuronate from UDP–glucuronic acid. Bilirubin diglucuronide (CB or direct bilirubin) is secreted into bile. Intestinal bacteria hydrolyze and reduce it to urobilinogen, most of which is oxidized to stercobilin, which colors feces. Some, however, is
reabsorbed into blood, taken up by liver, and secreted into bile (enterohepatic circulation). The remainder is transported to the kidneys, converted to yellow urobilin, and excreted.
[Note: Because CB is normally sent into the intestine, 95% of the total serum bilirubin is UCB.]
Heme Degradation 21 3.3
What is the difference between Dubin-Johnson and Crigler-Najjar I syndromes?
- *Dubin-Johnson syndrome** (benign) is caused by a rare deficiency in the protein that transports CB out of the liver, causing it to leak into blood and resulting in a conjugated (direct) hyperbilirubinemia.
- *Crigler-Najjar** I (severe) is a virtually complete deficiency of bilirubin UGT that results in an unconjugated (indirect) hyperbilirubinemia.
Jaundice 21 4.1
Deposition of what molecule is responsible for the yellow color of the sclerae shown, a condition known as jaundice ?
Jaundice ( icterus ) is caused by deposition of bilirubin secondary to hyperbilirubinemia.
Jaundice 21 4.2
What are the three major types of jaundice?
The three major types of jaundice are
(1) hemolytic (prehepatic) jaundice caused by
production of bilirubin in excess of the liver’s capacity to conjugate it, resulting in an unconjugated hyperbilirubinemia;
(2) hepatocellular ( hepatic ) jaundice caused either by bilirubin UGT deficiency, resulting in an unconjugated hyperbilirubinemia, or by impaired secretion of CB into bile, resulting in a conjugated hyperbilirubinemia; and
(3) obstructive (posthepatic) jaundice caused by common bile duct blockage, resulting in a conjugated hyperbilirubinemia.
[ Note: If less CB enters the intestine, stool is pale in color. The resulting increase in urinary
bilirubin darkens the urine. Only CB is found in urine because it is water soluble. UCB is not.]
Jaundice 21 4.3
Which type of jaundice is best represented by the figure?
the picture with yellow eyes.
Hepatocellular jaundice, caused by decreased hepatic production or secretion of CB, is
represented. [ Note: Physiologic jaundice of the newborn, a type of hepatocellular jaundice
caused by a transient developmental delay in bilirubin UGT expression, is seen in the majority of neonates. If UCB levels exceed the binding capacity of albumin, UCB can cross the BBB and cause a toxic encephalopathy known as kernicterus. Treatment includes phototherapy to convert bilirubin to a more water-soluble isomer.]
Catecholamines 21 5.1
What enzyme catalyzes the rate-limiting conversion of Tyr to DOPA, as shown?
What coenzyme does it require?
What coenzyme is required in the conversion of DOPA to dopamine?
Of norepinephrine to epinephrine?
Tyrosine hydroxylase converts Tyr to DOPA. As an aromatic amino acid hydroxylase, it requires THB as a coenzyme. The conversion of DOPA to
dopamine is catalyzed by aromatic amino acid decarboxylase, which requires PLP. The methyltransferase that converts norepinephrine to epinephrine
requires SAM.
[Note: Only the methylation of Hcy to Met uses THF.]
Catecholamines 21 5.2
What is the function of the norepinephrine and epinephrine (catecholamines) released from the adrenals in response to physiologic stress?
Catecholamines mediate the retrieval of energy-producing molecules from tissue stores in times of physiologic stress.
Catecholamines 21 5.3
Why might HVA levels be decreased in individuals with Parkinson disease ?
In Parkinson disease, the loss of dopamine-producing cells in the brain results in dopamine deficiency. Dopamine is degraded to HVA by COMT and MAO , so a deficiency results in decreased HVA generation.
[Note: COMT and MAO degrade epinephrine and norepinephrine to VMA.]
Other Nitrogen-Containing Compounds 21 6.1
What is the function of creatine phosphate, the synthesis of which from the amino acids Arg, Gly, and Met (as SAM) is shown?
Creatine phosphate provides a small, rapidly mobilized muscle
reserve of high-energy phosphate groups that can be transferred to
ADP to maintain ATP levels early in intense contraction. It spontaneously
cyclizes to creatinine, which is filtered by the kidney with little reabsorption. Elevated creatinine levels in the blood with low levels in the urine indicates impaired renal function.
