Biochemistry Heme & Iron Metab

Front 1

What is the rate-limiting step in heme synthesis?

Back 1

conversion of glycine and succinyl CoA into ALA (delta-aminolevulinc acid) by ALA synthase using pyridoxal phosphate cofactor

Front 2

Where within the cell does heme synthesis take place?

Back 2

mitochondria for the first and last three enzymatic steps
cytosol for rest

Front 3

What is the first step in heme synthesis?

Back 3

the rate limiting step producing ALA by ALAS (ALA synthase)

Front 4

What is the organic portion of heme derived from?

Back 4

eight residues each of glycine and succinyl CoA

Front 5

What intermediates are involved in the reactions on the side groups of the tetrapyrrole ring?

Back 5

colorless porphyrinogens - these are unstable and are readily oxidized (esp in light) nonenzymatically to stable porphyrin products

Front 6

What is the only enzymatic porphyrinogen oxidation to occur in humans?

Back 6

conversion of protoporphyrinogen to protoporphyrin by protoporphyrinogen IX oxidase in mitochondria during heme synthesis

Front 7

How can a type I porphyrinogen be identified?

Back 7

substituents of pyrrole group arranged ABABABAB clockwise around ring

Front 8

How can a type III porphyrinogen be identified?

Back 8

ABABABBA order of substituents on pyrroles clockwise around ring

Front 9

How many types of substituents do protoporphyrinogen and protophyrin have and which type occurs naturally?

Back 9

3 different kind of substituents but only type IX is naturally synthesized

Front 10

Where is aminolevulinic acid synthase synthesized?

Back 10

made in cytosol, a homodimer, and its basic N-terminal signaling sequence directs it to mitochondria

Front 11

How does ALA synthase pass into mitochondria?

Back 11

ATP-dependent cytosolic chaperone protein keeps it in unfolded extended state

Front 12

What happens to ALA synthase once it is in the mitochondrial matrix?

Back 12

- metal dependent protease cleaves N-terminal signaling sequence
- 14 subunit ATP-dependent chaperone protein catalyzes correct folding of the enzyme

Front 13

What isoforms do ALA synthase come in?

Back 13

- ALAS-E (ALAS-2) erythoid form
- ALAS-N (ALAS-1) nonspecific form

Front 14

What does a deficiency in ALAS-E cause?

Back 14

X-linked sideroblastic anemia

Front 15

What does aminolevulinic acid dehydratase do?

Back 15

asymmetrically condenses 2 ALA molecules to form porphobilinogen in CYTOSOL

Front 16

What is special about aminoevulinic acid dehydratase?

Back 16

contains zinc and is very sensitive to inhibition by heavy metals - esp lead - so in lead poisoning get elevated ALA but not elevated porphobilinogen

Front 17

How does porphobilinogen deaminase work?

Back 17

sulfhydryl group on enzyme forms thioether bond with porphobilinogen residue through deamination reaction

Front 18

What is porphobilinogen deaminase closely associated with?

Back 18

uroporphyrinogen III synthase

Front 19

What is erythropoietic porphyria?

Back 19

defective reticulocyte uroporphyrinogen III synthase so get larger amounts of the type I isomers and cutaneous light sensitization

Front 20

What does uroporphyringoen decarboxylase do?

Back 20

acts on side chains of both type I and III uroporphyrinogen to form corresponding coproporphyrinogen

Front 21

What inhibits uroporphyrinogen decarboxylase?

Back 21

iron salts

Front 22

What does coproporphyrinogen oxidase do?

Back 22

converts type III coproporphyringen into protoporphyrinogen IX in the mitochondria

Front 23

What is hereditary coproporphyria?

Back 23

form of hereditary hepatic porphyria associated with a dominantly inherited defected coproporphyrinogen oxidase

Front 24

What does protoporphyrinogen oxdase do?

Back 24

converts protoporphyrinogen IX into protoporphyrin IX which is very water insoluble, and excess excreted via biliary system

Front 25

What is variegate porphyria?

Back 25

dominant disease from a defect of protoporphyrinogen oxidase

Front 26

What does ferrochelatase do?

Back 26

inserts ferrous iron into protoporphyrin IX in last step of heme synthesis

Front 27

What does ferrochelatase require for its activity?

Back 27

reducing substrates

Front 28

What is ferrochelatase sensitive to?

Back 28

heavy metals (like ALA dehydratase) esp lead and iron deprivation
when iron is deprived zinc can be inserted into protoporphyrin IX which makes fluorescent compound

Front 29

What is the prosthetic group on ferrochelatase?

Back 29

Fe2S2

Front 30

How does heme regulate is synthesis?

Back 30

represses synthesis and inhibits the activity of ALA synthase
and inhibits ALA dehydratase but this is less important

Front 31

What is the immediate cause of porphyrias?

Back 31

underactivity of one the biosynthetic enzymes which results in decline of cellular heme levels and de-repression of ALA synthase activity

Front 32

Why do hereditary porphyrias appear after puberty?

Back 32

appearance of steroid 5-beta-reductase activity for sex hormone biosynthesis which then stimulates ALA synthase activity

Front 33

How does lead poisoning affect heme synthesis?

Back 33

inhibits ALA dehydratase get increse in ALA levels
inhibits ferrochelatase
coproporphyrin III gets excreted in urine

Front 34

What is acute intermittent porphyria?

Back 34

neurologic porphyria due to phosphobilinogen deaminase deficiency
delta-aminolevulinate and prophobilinogen excreted in urine

Front 35

What is congenital erythropoietic porphyria?

Back 35

cutaneous porphyria
decreased uroporphyrinogen III synthase activity - mainly affects erythropoietic tissue
uroporphyrin I and coproporphyrin I excreted

Front 36

Protoporphyria?

Back 36

cutaneous porphyria
low ferrochelatase so protoporphyrin IX excreted in feces
affects liver and erythropoietic tissues

Front 37

What are the mixed porphyrias?

Back 37

neurologic and skin symptoms
-variegate porphyria - dec protoporphyrinogen oxidase, high urinary coproporphyrins, affects liver
-coproporphyria - coproporphyrinogen oxidase activity dec, inc urinary coproporphyrins

Front 38

Which enzymes use heme as part of prosthetic group?

Back 38

-catalase
-peroxidase
-tryptophan pyrrolase
-prostaglandin synthase
-guanylate cyclase
-NO synthase
-microsomal and mitochondrial cytochromes

Front 39

What are non-heme proteins?

Back 39

transferrin
ferritin
redox enzymes with iron at active site
iron-sulfur proteins

Front 40

What does the H chain of ferritin do?

Back 40

oxidizes ferrous ions (2+) to the ferric state (3+) by endogenous ferroxidase activity
-facilitates storage because to leave ferritin molecule Fe(III) must be reduced to Fe(II)
-H chain predominates in nucleated blood cells and heart

Front 41

How is transferrin biosynthesis regulated?

Back 41

transcription level

Front 42

How are ferritin and transferrin receptor genes regulated?

Back 42

at translational level
ferritin has IRE at 5' end
TfR mRNA has IRE at 3' end

Front 43

What is ferroportin 1?

Back 43

duodenal iron exporter on basolateral surface of mucosal cell
-transfers ferrous ions out of cell into circulation to transferrin

Front 44

What is ceruloplasmin?

Back 44

ferroxidase that may be involved in oxidizing ferrous iron to the ferric form before it is loaded onto transferrin from the duodenal cell

Front 45

Where is iron homeostasis strictly regulated?

Back 45

intestinal absorption

Front 46

Which cells have a high level of transferrin receptors?

Back 46

heart, liver, thyroid, gonads, pancreatic islets

Front 47

What is well characterized in patients with hereditary hemochromatosis?

Back 47

iron overload syndromes

Front 48

What is the best indirect biochemical marker of iron stores?

Back 48

TS transferrin saturation