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Biochemistry > Synthesis Of Heme > Flashcards

Synthesis Of Heme Flashcards

1
Q

Porphyrins

A

. Cyclic compounds
. Bind to metal ions (ferrous or ferric ions)
. Formed by linkage of 4 pyrrole rings through methenyl bridges
. Pigmented

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2
Q

Ferrous

A

Fe2+

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3
Q

Ferric

A

Fe3+

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4
Q

How many types of porphyrins are there and what ones are important to humans?

A

4 types, type III important because it contains asymmetric substitution of ring D
. Type I may be synthesized in disease process

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5
Q

Porphyringogens

A

. Porphyrin precursor
. Colorless
. Intermediates heme biosynthesis
. Exists in chemically reduced forms

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6
Q

Heme

A

. Final product of porphyrin synthetic pathway

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7
Q

What protoporphyrin is important to humans and why?

A

Type IV because one Fe2+ in center is what heme is

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8
Q

Heme biosynthesis sites

A

Liver and erythrocyte- producing cells of bone marrow

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9
Q

Where do reaction steps of heme biosynthesis occur?

A

. Initial and last steps of porphyrin formation are in mitochondria
. Intermediate steps in cytosol

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10
Q

Hemin

A

. End product inhibitor
. Inhibits formation of aminolevulinic acid (ALA) by decreasing ALA synthase enzyme synthesis
.Overall heme synthesis inhibited because not enough ALA synthase to make ALA for synthesis
. Result of oxidation of Fe2+ to Fe3+ when excess heme accumulates

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11
Q

Drugs that increase ALA synthase activity

A

Drugs that affect Heme-containing microsomes cytochrome P-450 mono-oxygenase system (barbiturates, sedatives, estrogens)

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12
Q

How do drugs using microsomal cytochrome P450 mono-oxygenase system increase ALA synthase activity?

A

. Through de-repression
. Major pathway for hydroxylation and detoxification of aromatic/aliphatic compounds
. Drugs need to be metabolized via this pathway so more cytochrome P450 is needed and contains heme
. P450 synthesis inc., more heme consumed in lever, less free heme available, inc. ALA synthase activity and dec. hemin

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13
Q

What does lead inhibit and how?

A

. Formation of porphobilinogen and formation of heme
. Inhibits ALA dehydratase elevating ALA and anemia
. Inhibits ferrochelatase

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14
Q

ALA dehydratase

A

Enzyme that catalyze formation of porphobilinogen

. Inhibited by lead

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15
Q

Ferrochelatase

A

Enzyme that enhances the incorporation of Fe2+ into protoporphyrin IX

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16
Q

Porphyria

A

. Autosomal dominant (exp. congenital one that’s recessive) Disorders of specific enzymes in heme biosynthesis
. Often autosomal dominant disorders
. Nonspecific
. Decreased heme synthesis
. Increased ALA synthase and heme intermediate production prior to the mutated enzyme

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17
Q

How are porphyria classified?

A

Hepatic or erythopoietic depending on whether enzyme deficiency occurs in RBC precursors in bone marrow or liver

18
Q

ALA and porphobilinogen accumulation symptoms

A

Abdominal pain and neuropsychiatric disturbances

Acute intermittent porphyria has these

19
Q

Photosensitivty cause

A

. Enzyme defects that lead to accumulation of tetrapyrrole intermediates
. Porphyrin-mediated formation of superoxide radicals (ROS) from oxygen
. ROS damages membranes and releases lysosomes

20
Q

Photosensitivity symptoms

A

. Skin itches and burns when exposed to visible light

21
Q

Porphyria treatments

A

. IV hemin injection (inhibits ALA synthase eventually dec. intermediates that built up)
. Avoidance of sunlight
. Ingestion of beta-carotene (free radical scavenger) help when experiencing photosensitivity

22
Q

Porphyrin accumulation cutaneous symptoms

A

. Skin or urine that is red to brown in natural light but pink to red in fluorescent light

23
Q

Lead poisoning

A

. Elevated ALA in urine
. Can cause anemia is lead level >40 mg/dL
. Affect IO, attention span, and academic achievement in kids that can’t be corrected
. Inc. protopoyphyrin IX in blood bc Fe 2+ can’t be put on to form full heme

24
Q

Lead level cutoff for ages 1-5

A

5 micrograms/dL

25
Q

Signs and symptoms of lead poisoning

A

. Stomach aches, cramping, constipation and diarrhea
. Nausea. Vomiting
. Persistent unexplained fatigue
. Headache
. Muscle weakness
. Long-lasting effects, coma, and death is leve >80 mcg/dL

26
Q

T/F patients w/ chronic low levels of lead exposure have no obvious symptoms

A

T

27
Q

What therapy is used in attempt to remove lead?

A

Chelation therapy

28
Q

Porphyria cutanea tarda

A

. Chronic, uroporphyrinogen decarboxylase deficiency (UROD)
. Uroporphyrin accumulates in urine
. Most common, usually acquired
. Those w/ UROD genetic deficiency (familial PCT) won’t have symptoms unless large amts porphyrins build in liver then disease becomes active
. Photosensitive
. Onset: 4-5th decade of life

29
Q

Acute intermittent porphyria

A

. Acute, porphobilinogen deaminase deficiency
. Porphobilinogen and ALA accumulates in urine
. Urine darkens on exposure to light or air
. NOT photosensitive
. 2nd most common, autosomal dominant, 5-10 of every 10,000 have it

30
Q

Rate limiting step in heme synthesis

A

. Glycine + succinyl CoA form ALA via ALA synthase

31
Q

ALA

A

Gamma aminolevulinic acid

32
Q

Heme pathway

A
  1. Gly + succinyl CoA -> ALA via ALA synthase
  2. ALA x2 -> porphobilinogen via dehydration rxn
  3. Porphobilinogen x4 -> uroporphyrinogen III via condensing rxn
  4. Uroporphyrinogen II -> protoporphyrin IX
  5. Fe 2+ introduced to make heme via ferrochelatase
33
Q

How to test for porphyria

A

. Quantifying different metabolites

. Screening at genetic level

34
Q

Porphyria symptoms

A

. Abdominal pain, neuropsychiatric disturbances (anxiety to delirium)
. Photosensitivity

35
Q

Porphyria cutanea tarda clinical expression influenced by __

A 
. Fe 
. Sunlight
. alcohol
. Estrogen
. Hep B/C, HIV
. Smoking
36
Q

What can predispose people to PCT

A

Hemochromatosis (Fe overload disorder)

37
Q

PCT symptoms

A

. Chronic recurring blisters on sun exposed areas
. Skin sensitive to minor injury
. Hair growt on face and other sun exposed areas increases
. Mild liver function abnormalities
. Cirrhosis or liver cancer may develop

38
Q

Acquired PCT treatments

A

. Avoiding alcohol

. Phlebotomy

39
Q

Acute hepatic porphyrias

A 
. ALA dehydratase deficiency porphyria 
. Acute intermittent porphyria
. Hereditary coproporphyria 
. Variegate porphyria 
. GI symptoms, neuropsychiatric, motor, photosensitivity
40
Q

AIP treatment

A

. Medical support
. Glucose
. Injection of hemin to dec. ALA synthase synthesis
. Avoid barbiturates, alcohol

41
Q

Erthyropoietic porphyrias

A

. Congenital erythropoietic porphyria
. Causes skin rashes and blisters
. May be at risk for hepatobiliary disease

Biochemistry (64 decks)

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