3 Biochem - Lec 22 Heme

Front 1

The porphin ring is a ______ structure

Back 1

- tetrapyrrole

Front 2

Heme is type III_________ with a coordinated iron atom

Back 2

- protoporphyrin

Front 3

What is the difference between uroporhyrin type I & type III?

Back 3

- differ in order of substituents on ring D

Front 4

A _______ oxidizes spontaneously to a Porphyrin

Back 4

- PorphyrinOGEN (intermediates in heme synthesis)

Front 5

Which cells synthesize heme?

Back 5

- all cells synthesize heme, majority from erythrocyte precursors in bone marrow & liver

Front 6

What 3 things is heme used in?

Back 6

1) hemoglobin
2) cytochromes
3) catalase / peroxidase

Front 7

First step of heme synthesis: _______ + ______ via ________ --> ________. Where does this reaction occur?

Back 7

- succinyl CoA + Glycine

- aminolevulinate synthase (ALA synthase)

- ALA

- reaction occurs in the mitochondria

- this is the regulated step --> product is transported into the cytoplasm

Front 8

In the second step of heme synthesis: two molecules of ______ are condensed by ______ to make ________ (a pyrrole). This product is colorless, but becomes colored on ________. What is special about this enzyme?

Back 8

- ALA (delta-aminolevulinate)

- delta-aminolevulinate dehydratase

- porphobilinogen

- oxidation

- zinc containing enzyme so subject to lead poisoning

Front 9

In the third step of heme synthesis, the first part requires 4 molecules of _____ to be condensed by ________. In the second part, ______ assures closure into _______.

Back 9

- porphobilinogen

- porphobilinogen deaminase (or uroporphyrinogen synthase)

- uroporhyrinogen co-synthase

- uroporphyrinogen type III

Front 10

Without uroporphyrinogen co-synthase, what happens?

Back 10

- ring closes to make uroporphyrinogen type I --> this can be converted to coproporphyrinogen, but not protoporhyrinogen

- type I will spontaneously oxidize to uroporphyrin type I = conjugated double bond system = colored red-brown --> deposits in skin & leads to photosensitivity

Front 11

In the fourth step of heme synthesis, uroporphyrinogen III is converted to ______ by ________. This molecule re-enters the ______.

Back 11

- coproporphyrinogen

- uroporphyrinogen decarboxylase

- mitochondria

Front 12

In the fifth step of heme synthesis: coproporphyrinogen III is converted to ________ by _________.

Back 12

- protoporphyrinogen III

- coproporphyrinogen decarboxylase

Front 13

After protoporphyrinogen is created, _______ makes ________.

Back 13

- protoporphyrinogen oxidase

- protoporphyrin

Front 14

Iron is captured by _____ in protoporphyrin to make ______.

Back 14

- ferrochelatase

- heme

Front 15

In the liver: ______ is the key regulated enzyme. ____ is they key feedback regulator, what does it do (4 things)?

Back 15

- ALA synthase 1 (ALAS1)

- heme

1) inhibits synthesis of ALAS1 by decreasing stability of mRNA (insulin decreases transcription, steroids increase synthesis)

2) inhibition of ALAS1 transport into the mitochondria

3) allosteric inhibition of ALAS1 by heme in mitochondria

4) drugs up regulate P450s increase heme synthesis

Front 16

In immature erythrocytes: Mature erythrocytes do not contain mito, so they do not synthesize ____. What 4 ways does it differ from liver regulation?

Back 16

- heme

1) iron increases translation of ALAS2 (removes inhibitor from mRNA)

2) iron increases ferrochelatase activity

3) erythrocyte-specific TFs act on ALAS2 gene promoter

4) inhibition of ALAS2 transport into mitochondria (heme)

Front 17

What happens in porphyrias (what builds up)? What is therapy?

Back 17

- accumulation of toxic intermediates until point of defect

- decrease activity of ALAS (no steroid hormones)

- no P450 reactive drugs b/c decrease free heme leading to increased ALAS

Front 18

What step is when you start to get skin photosensitivity?

Back 18

- uroporphyrinogen

- everything after this (including this) is insoluble

- skin sensitivity to tetrapyrroles

Front 19

What is the best way to diagnose a porphyria? Treatment?

Back 19

- urine PBG test

- analysis of excreted: ALA, PBG, uroporphyrinogen (urine), uroporhyrinogen, copro, proto (stool)

- decrease ALAS activity, glucose, no P450 drugs

Front 20

Porphyrias are characterized by high levels of __________ (and synthase activity) and by intermediates up to the deficiency (test: urine_____)

Back 20

- d-aminolevulinic acid (ALA)

- PBG

Front 21

difference between congenital (hereditary) and acquired porphyria? What tissues are usually affected?

Back 21

- congenital shows up

- acquired shows symptoms when confounding factors present

- neurological problems

Front 22

Acute intermittent porphyria

Back 22

- PBG deaminase deficiency

- porphobilinogen --> porphobilin

- urine turns purple

Front 23

Porphyria cutanea tarda

Back 23

- uroporphyrinogen decarboxylase deficiency

- uroporphyrinogen --> uroporphyrin III

- vampire disease

- photosensitive, not soluble

Front 24

Heme is broken down by mixed function oxidase, a _______ enzyme system

Back 24

- cytochrome P450

Front 25

When heme is broken down it is converted to ______ (green) then converted to ______ (yellow-brown)

Back 25

- biliverdin

- bilirubin

- accumulation fo bilirubin = jaundice

Front 26

Liver disease: accumulation of________, Excessive hemolysis: accumulation of_______, Occlusion of bile duct: accumulation of ________. Which enzyme conjugates bilirubin?

Back 26

- non-conjugated bilirubin

- non-conjugated bilirubin

- conjugated-bilirubin

- diglucuronyl transferase

Front 27

why do newborns get jaundice? How do you treat?

Back 27

- maternal liver normally metabolizes heme produced by fetus

- expression of DUP-glucuronyl transferase occurs after birth

- light therapy can help remove bilirubin - make it more soluble and hydrophilic