Heme Biosynthesis Flashcards
1
Q
Formed by linking 4 pyrole rings
A
Heme
2
Q
What are the three types of side chains that can be attached to the pyrrole ring?
-arangment of side chains is important to activity
A
Methyl, vinyl, or propionate
3
Q
What are the major components of Heme?
A
- ) 4-linked pyrrole
- ) 3 types of side chain
- ) Prosthetic group for proteins (tightly-bound cofactor)
- ) Chelated Fe2+
4
Q
Heme produced in the liver is used mainly for the synthesis of the
A
cytochrome P450 class of enzymes
5
Q
Responsible for phase I liver detoxification and for detoxifying xenobiotic sources of toxicity, chemicals, acohols, and carcinogens
A
Liver Cytochrome P450
6
Q
When liver Cytochrome P450 detoxifies xenobiotic sources of toxicity, chemicals, acohols, and carcinogens, what does it convert them into?
A
Water and Oxygen
7
Q
What is responsible for bilirubin metabolism, synthesis of vitamin D, cholesterol synthesis, and synthesis of bile and bile acids?
A
Liver Cytochrome P450
8
Q
What are the porhpyrin precursors and what are their characteristics?
A
Aminolevulinate(ALA) and Porphobilinogen (PBG)
- water soluble
- excreted and measured in urine
- biologically inactive
9
Q
Larger molecules whose aqueous solubility varies in part based on the number of carboxylic acid side chains in the molecule
A
Porphyrinogens
10
Q
Are porphyrinogens biologically active?
A
Yes
11
Q
Excreted in urine
A
Uroporphryinogen
12
Q
Much less water soluble than uroporphyrinogen and is excreted in the feces as well as in urine
A
Coproporphyrinogen
13
Q
Excreted and measured in feces
A
Stercoporphyrinogen
14
Q
Molecules detected and measured in clinical laboratories
-Oxidized
A
Porphyrins
15
Q
The oxidation of porphyrins creates an extended conjugation system that allows the molecules to
A
Absorb visible light
16
Q
Oxidation of porphyrins in the cell is dangerous because the release of the absorbed light produces
A
Reactive oxygen species
17
Q
Heme biosynthesis takes place in the
A
Cytoplasm and mitochondria
18
Q
How many enzymes catalyze heme biosynthesis?
A
8
19
Q
The first and last two steps of heme biosynthesis take place in the
A
Mitochondria
20
Q
What have the highest rates of heme biosynthesis?
A
Bone marrow erythroid cells and the liver
21
Q
85% of heme is synthesized in
A
Bone marrow erythroid cells
22
Q
85% of heme is synthesized in bone marrow erythroid cells because
A
Mature RBC’s lack mitochondria, thus heme synthesis stops upon maturity
23
Q
Mitochondira are progressively lost throughout erythroid maturation through
A
Autophagy
24
Q
What is the committed step of heme biosynthesis?
A
Step 1:
Succinyl CoA + Glycine —> delta ALA
25
The committed step of Heme biosynthesis is catalyzed by?
ALA synthase (ALAS 1 (liver) and ALAS 2 (erythroid cells))
26
What happens in the first step of Heme biosynthesis?
- Committed step
- Highly regulated
δ-ALA is formed in the mitochondria and transported to the cytoplasm
27
In the second step of Heme biosynthesis, 2 molecules of ALA condense to form
Porphobilinogen (PBG)
28
The second step of heme biosynthesis is catalyzed by
-Zinc containing enzyme
ALA dehydratase (PBG synthase)
29
ALA dehydratase is inhibited by?
Lead
30
The first precursor to pyrrole is synthesized in the
2nd step
31
In the third step of heme biosynthesis, 4 molecules of PBG are joined into an extended linear tetrapyrrole (hydroxymethylbilane). This reaction is catalyzed by?
PBG deaminase
32
Once synthesized, hydroxymethylbilane has what two main fates?
1. ) Converted to Uroporphyrinogen III (URO III Synthase) then to Coproporphyrinogen III (URO III decarboxylase)
2. ) At high concentrations, a spontaneous reaction occurs converting it to URO 1 and then COPRO 1
33
Catalyzes an intramolecular rearrangement and ring closure
URO III synthase
34
Following a series of decarboxylation and oxidation reactions, Coproporphyrinogen III is converted into
Protoporphyrin IX
35
Protoporphyrin IX is converted into Heme by
Ferrochelatase
36
A mitochondrial enzyme that adds an Fe2+ to protoporphyrin IX to form Heme
Ferrochelatase
37
Ferrochelatase is inhibited by
Lead
38
What are the three porphyrins generated in heme biosynthesis (and where are they excreted)
1. ) Uroporphyrin (urine)
2. ) Coproporphyrin (Urine and bile)
3. ) Protoporphyrin (Bile)
39
Water solubility decreases due to decarboxylation steps as the pathway progresses towards heme. Thus excretion progresses from
Urine (uroporphyrin: 8 carboxylates) to bile (protoporphyrin: 2 carboxylates)
40
What are the three mechanisms of regulation of ALAS 1 (the committed step enzyme) in the liver?
1. ) Allosteric feedback
2. ) Inhibition of newly synthesized ALAS from cytosol to mitochondria
3. ) Repression of transcription of ALAS
41
What provides allosteric feedback to regulate ALAS 1 in the liver?
Heme, Hemin*, and hematin*
*pharmologically by stable forms of heme
42
What inhibits the newly synthesized ALAS protein transport from cytosol to mitochondria?
Heme
43
What represses the transcription of ALAS?
Heme, Glucose, and Insulin
44
What serves as an activator to induce ALAS-1 transcription?
-a coactivator of nuclear receptors and transcription factors
Peroxisome proliferator-activated receptor ƴ coactivator 1α (PGC-1α )
45
Inhibit PCG-1α, thereby inhibiting ALAS transcription
Heme, Insulin, and Glucose
46
What are the "4M's" that induce transcription of ALAS 1?
1. ) Medication
2. ) Menstruation
3. ) Malnutrition
4. ) Maladies (stress, trips, exams)
47
Certain medications are metabolized by cytochrome P450 enzymes, which are hem-containing proteins. What effect then do certain drugs have on heme synthesis?
Induce the synthesis of cytochrome P450, thus leading to an increased demand for heme
48
The increased demand for heme caused by induced synthesis of Cytochrome P450 leads to
An overall decrease of heme in the liver and subsequent transcription of ALAS synthase and heme synthesis
49
Low iron cellular content through and iron response element sequence (IRE) results in the
Repression of translation of ALAS2
50
Describe how low iron cellular content through an IRE represses transcription
The IRE forms a translational blockade that prevents iron from binding translational machinery
51
ALAS 1 catalyzes the first step of heme synthesis in the
Liver
52
ALAS 2 catalyzes the first step of heme synthesis in the
Erythroid cells
53
What are three abnormalities in Heme synthesis
1. ) Sideroblastic anemia
2. ) Lead (Pb) poisoning
3. ) Porphyias
54
Heterogeneous group of disorders with 2 common features
Sideroblastic Anemia
55
What are the two common features of sideroblastic anemia?
1. ) Ring sideroblasts in the bone marrow
| 2. ) Impaired heme biosynthesis
56
Abnormal normoblasts with excessive accumulation of iron in the mitochondria
Ring sideroblasts
57
Results in mture red blood cells that are smaller than normal (microcytic) and appear pale (hypochromic) because of the shortage of hemoglobin
Sideroblastic anemia
58
Sideroblastic anemia disturbs
Mitochondrial metabolism
59
What is the major hereditary sideroblastic anemia and what is it's etiology (cause)
Congenital X-linked sideroblastic anemia: caused by ALAS-2 mutation
60
What are three ways to aquire sideroblastic anemia (SA)?
1. ) Drugs (isoniazid for tuberculosis or ethanol)
2. ) Toxins (lead)
3. ) Nutritional (pyridoxine deficiency)
61
Lead inhibits which two key enzymes in heme synthesis?
ALA dehydratas(ALAD) and Ferrochelatase
62
Which is more sensitive to the effects of lead, Ferrochelatase or ALAD
ALAD
63
How can you treat lead induced sideroblastic anemia?
-bind lead and help it be excreted in urine
Lead chelators
64
What is a moderate in severity presentation of lead poisoning?
Gingival and long bone lead lines
65
What is a more sever consequence of lead poisoning?
Renal failure
66
What are three ways we can diagnose lead poisoning?
1. ) Accumulation of ALA in urine
2. ) Zinc protoporphyrin (ZPP) in the blood
3. ) Basophilic stippling in peripheral smear
67
The accumulation of ALA in the urine, which indicates lead poisoning, is due to
ALAD inhibition
68
The presence of Zinc protoporphyrin (ZPP) in the blood, which indicates lead poisoning, is due to the fact that
In the absence of iron, iron can not be chelated into protoporphyrin IX, so Zn substitutes for Fe
69
Pathologies stemming from defects in heme biosynthesis
Porphyrias
70
Most porphyrias behave as
Autosomal dominant genetic diseases
71
What are three porphyrias in heme biosynthesis and which steps do they occur?
1. ) Acute intermittent porphyria (step 3)
2. ) Porphyria cutanea tarda (step 5)
3. ) Erythropoietic protoporphyria (step 8)
72
Clinical presentations of Porphyrias differ. They could be presented by a deficient
Enzyme
73
The accumulation of heme biosynthesis intermediates such as ALA and PBG could indicate
Acute Porphyria
74
Accumulation of porphyrinogens in the skin and tissues could indicate
Non-acute porphyria
75
The second most common type of porphyria
Acute intermittent Porphyria (AIP)
76
Acute intermitent Porphyria (AIP) is caused by a
Partial deficiency in PBG deaminase (PBGD)
77
The accumulation of ALA and/or PBG can result in peripheral neuropathy and nerovisceral symptoms, which indicate
Acute intermittent Porphyria (AIP)
78
Unlike other porphyrias, AIP does not result in
Skin lesions
79
Only 10% of people with AIP develop disease, but all are at risk for
Primary liver cancer
80
Clinical expression of AIP occurs in response to 4Ms that decrease the livers concentration of
Heme
81
What is the consequence of the decrease in cellular levels of heme seen in AIP?
Feedback inhibition on ALA synthase is reduced, resulting in more heme biosynthesis
82
With AIP, your urine becomes a dark-brown color. This is the result of
PBG in urine which gets oxidized to porphobilin upon being exposed to air
83
What are three treatment options for AIP?
1. ) Avoid precipitating factors (4Ms)
2. ) Glucose loading
3. ) Administer HEmin/Hematin (inhibit ALAS synthase)
84
What is the most common type of Porphyria?
Porphyria cutanea tarda (PCT)
85
PCT results from a deficiency of the hepatic enzyme
Uroporphyrinogen decarboxylase (UROD)
86
Essentially an aquired disease, but some individuals have a genetic (autosomal dominant) deficiency of UROD, which contributes to its development
Porphyria cutanea tarda (PCT)
87
Genetic PCT is referred to as
Familial PCT
88
The clinical onset of PCT typically occurs during the
4th or 5th decade of life
89
What types of factors can influence the expression of UROD and subsequently cause PCT?
Alcohol, Hepatic iron overload, sunlight, hep B or C, hydrochlorobenzene
90
What are some symptoms of PCT?
1. ) Bullae
2. ) Hypertrichosis
3. ) Heliotropic facial skin
4. ) sclerodermoid plaque on scalp
91
Blisters filled with clear fluid
Bullae
92
Purple-red suffusion facial skin
Heliotrope facial skin
93
Tiny white bumps or small cysts on the skin which can also represent PCT
Milia
94
What causes one of the major signs and symptoms or porphyrias: photosensitivity?
The ring shaped intermediates which are reactive w/ light and form oxygen radicals
95
Leads to local tissue damage (on sun exposed skin) including itching and burning sensations and rash-like appearance
Photosensitivity caused by porphyrias
96
One of the ways to detect PCT is through the coral red fluoresence of urine, caused by
Uroporphyrin to cproporphyrin ratios ranging from 3:1 to 5:1
97
To detect PCT, the fractionation of serum porphyrins can be performs. What would indicate PCT?
A predominance of 7-8 carboxyl porphyrin fractions reflecting a UROD defect
98
How can PCT be detected in red blood cells?
UROD enzyme activity assay
99
What are two clinical treatments of PCT?
1. ) Chelation with an iron chelator
| 2. ) Phlebotamy (bleeding)
100
Reduces iron stores, which improves heme synthesis disturbed by iron mediated inhibition of UROD
Phlebotamy
101
Erythropoetic Protoporphyria is caused by mutations in
Ferrochelatase
102
Has an autosomal dominant inheritance and is present in early childhood
-indicated by severe cutaneous photosensitivity
Erythropoetic Protoporphyria (EPP)
103
Later in life, EPP results in
Chronic liver disease
104
Iron inhibits
-Causes PCT
UROD
105
Which is the only Porphyria that can be acquired and is not genetic?
PCT
106
Iron inhibits
-Causes PCT
UROD
107
Which is the only Porphyria that can be acquired and is not genetic?
PCT
108
What role does vitamin B6 provide in heme biosynthesis?
Vitamin B6 is a cofactors for ALAS
109
Stimulates ALAS2 in erythroid cells
Iron
110
When an enzyme of heme biosynthesis is inhibited, what is actually excreted and detected to show inhibition?
Porphyrins. The inhibition causes accumulation of porphyrinogen, which is oxidized to porphyrin and then excreted
