Biochemistry - Heme

Question 1

What is the difference between a porphyrin and a porphyrinogen?

Answer 1

Porphyrins have conjugated double bonds, porphyrinogens are reduced (without conjugated double bonds)

Question 2

What cells synthesize heme?

Answer 2

Almost all cells

Question 3

Which two tissues synthesize the majority of heme for the body? What proportions of heme do these tissues produce, respectively?

Answer 3

Bone marrow makes 85%, liver makes 15%

Question 4

What is the first, rate-limiting and regulated step of heme synthesis? (name the reactants, enzyme, and product)

Answer 4

Succinyl coA + glycine produces delta-aminolevulinate (delta-ALA). The enzyme is delta-ALA synthase.

Question 5

How is delta-ALA synthase 1 regulated by heme in the liver?

Answer 5

Heme allosterically inhibits the enzyme, decreases its transport from the cytoplasm to the mitochondria, and decreases delta-ALA’s mRNA stability.

Question 6

In what organ is delta-ALA synthase 1 found?

Answer 6

Liver

Question 7

In which subcellular location does the first reaction of heme synthesis occur?

Answer 7

Mitochondrial matrix.

Question 8

Which reaction does lead poisoning inhibit in the heme synthetic pathway?

Answer 8

The second reaction, which combines 2 delta-ALAs to make porphobilinogen. The enzyme of this reaction (delta-ALA dehydratase) is zinc containing, and lead outcompetes zinc.

Question 9

Which intermediate is the first intermediate in heme synthesis that is not water soluble, and therefore excreted in the feces rather than in urine?

Answer 9

Coproporphyrinogen type III is the first water insoluble intermediate (side chain acetic acid —> methyl) and is excreted in the feces.

Question 10

What effect on heme synthesis does upregulation of Cytochrome P450 have? Does this affect ALAS-1 or ALAS-2?

Answer 10

It increases heme synthesis through ALAS-1.

Question 11

How do insulin and steroid hormones regulate delta-ALA synthase 1?

Answer 11

Insulin decreases its transcription, steroid hormones increase enzyme synthesis (somehow - he didn’t say how)

Question 12

What happens when there is a defect in uroporphyrinogen co-synthase?

Answer 12

A and P side chains are not flipped on a pyrrole ring (ring D), resulting in a biologically inactive Type I uroporphyrinogen. This gets oxidized to Type I uroporphyrin, resulting in its deposit in skin - photosensitivity. Also leads to neurologic symptoms.

Question 13

Where is delta-ALA synthase II found?

Answer 13

Bone marrow.

Question 14

How does glucose help relieve symptoms of porphyrias?

Answer 14

Glucose results in increased levels of insulin, which inhibits the synthesis of delta-ALA synthase 1, resulting in decreased pathway activity, lowering levels of the toxic, defective byproduct.

Question 15

What are the intermediates of heme breakdown in macrophages?

Answer 15

Hemoglobin –> biliverdin (green) –> bilirubin (yellow)

Question 16

Where does bilirubin go after macrophages break down heme? Does it require a protein carrier?

Answer 16

Serum albumin takes bilirubin to the liver.

Question 17

How does fluorescent light help newborns deal with bilirubin? What enzyme is lacking?

Answer 17

Baby livers don’t make diglucuronyl transferase until weeks after birth. Bilirubin can form intramolecular H-bonds between proprionic acid side chains due to isomerization about a double bond - this isomer is insoluble. Light breaks these bonds to allow babies to excrete bilirubin in urine.

Question 18

A bile duct obstruction can result in the build-up of which bilirubin breakdown product?

Answer 18

Conjugated bilirubin.

Question 19

The accumulation of bilirubin causes what condition? What are two potential causes?

Answer 19

Jaundice. Possible causes are liver disease (no conjugation), or excessive hemolysis.

Question 20

What is the defect in acute intermittent porphyria? Why is the disease intermittent? What prominent person had this disease?

Answer 20

Cannot make uroporphyrinogen III from porphobilinogen. It is intermittent because porphobilinogen is water soluble and builds up only under certain conditions to cause symptoms. King George had this. He had purple urine because oxidized porphobilin is purple.

Question 21

Is globin synthesis coupled to heme transcription factors in the bone marrow?

Answer 21

Yes.

Question 22

What is the defect in phorphyria cutanea tarda? What results?

Answer 22

Cannot do uroporphyrinogen III –> coproporphyrinogen III (decarboxylase enzyme). Vampires result.

Question 23

Are porphyrias congenital diseases?

Answer 23

Yes.

Question 24

What are the three classes of porphyrias?

Answer 24

Erythropoietic and hepatic (congenital), and acquired (underlying defect doesn’t result in symptoms until chemicals such as drugs increase delta-ALA synthase activity)

Question 25

What is the name of the first tetrapyrrole in heme synthesis?

Answer 25

Uropophyrinogen type III (or I with defective co-synthase)

Question 26

How does heme regulate ALAS-2?

Answer 26

Inhibits its transport into the mitochondria.

Question 27

How does iron regulate heme synthesis? In which organ does this regulation occur primarily?

Answer 27

Fe2+ increases ALAS-2 (bone marrow) translation and increases ferrochelatase activity.