07a: Heme/BR Metabolism Flashcards by Nuna H

The rate-limiting step in heme biosynthesis involves (X) enzyme. What are the reactants/products?

X = ALA synthetase

R: Glycine and succinyl-CoA
P: ALA

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Most heme in cells is (free/bound) because of its (low/high) water solubility.

Bound (forming hemoproteins);

Low

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Even the slightest under-production of (X) results in disregulation of heme biosynthetic pathway and (over/under)-production of (Y). Why?

X = heme;
Over-production
Y = intermediates

Heme regulates its own synthesis (so low levels will ramp up pathway)

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In normal individuals, heme degradation results in (X); principally and specifically in mammals, (Y).

X = bile pigment
Y = bilirubin

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BR is produced from (X) in (Y) cells. What’s its immediate fate/destination afterwards?

X = heme (degradation)
Y = Mononuclear phagocytic system (MPS)

Transported in blood (via albumin) to liver

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In (X), BR undergoes conjugation with (Y), making it the (more/less) water-soluble form, (Z). It’s ready for secretion.

X = liver
Y = glucuronic acid
More
Z = BR Diglucuronide (BRDG)

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T/F: Free BR is secreted in minute amounts in from liver to bile.

False - can’t be secreted; very water-insoluble

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Jaundice is simply (deficit/excess) (X) in (Y).

Excess (failure to remove);
X = BR
Y = blood

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The intermediates in the heme biosynthetic pathway are collectively called (X) and have (Y) color.

X = porphyrinogens;
Y = no

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Porphyrins are (oxidized/reduced) forms of (X).

Oxidized;

X = Porphyrinogens

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(Porphins/porphyrins/porphyrinogens) are colored and most fluorescent under UV light.

Porphyrins

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Primary sites of heme biosynthesis are:

Liver and bone marrow

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List the heme biosynthesis intermediates in order.

ALA
PBG
Bilane
Uro’gen III
Copro’gen III
Proto’gen IX
Protoporphyrin IX
Heme

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The final step in heme synthesis is carried out by (X) enzyme. (Y) becomes heme following which change by (X)?

X = ferrocheletase
Y = protoporphyrin IX

Addition of Fe (ferrous) ion

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First step of heme biosynthesis is (synthesis/combination) of (X), which then combines with (Y).

Synthesis;
X = Y = ALA

(ALA synthesized, then combines with one other ALA molecule)

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(2/4/6) ALA molecules come together to form (X), which then combine with (2/4/6) (Y).

2;
X = Y = PBG

(2 ALA form PBG; 4 PBG combine in linear manner)

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Heme biosynthesis: (2/4/6) molecules of PBG combine in (linear/ring) fashion, forming (X). In non-enzymatic state, (X) rearranges into (Y) shape.

4; linear
X = bilane
Y = ring

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Heme biosynthesis: bilane forms (X) in non-enzymatic state and (Y) if acted on by uro’gen cosynthase. What’s the difference between X and Y?

X = uro'gen I (APAPAPAP)
Y = uro'gen III (APAPAPPA)

Side chain order switched in uro’gen III

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Heme biosynthesis: a series of (carboxylations/decarboxylations) makes later intermediates more (hydrophobic/hydrophilic).

Decarboxylations (of uro’gen and copro’gen);

Hydrophobic

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Heme biosynthesis: proto’gen undergoes which changes to become (X)?

Oxidation;

X = protoporphyrin

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Which steps in heme biosynthesis occur in cytoplasm? The rest occur in (X).

2, 3, 4, 5

X = mitochondria

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Heme regulates its own synthesis. List the 4 mechanisms by which it does this.

Feedback inhibition of ALA synthase
Aporepressor in nucleus (inhibits ALA synthase transcription)
Inhibit translation of ALA S.
Binds ALA S. in cytoplasm and blocks its entry into mito

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Heme catabolism: what’s are the two primary sources of heme anyway?

Senescent erythrocytes

2. Hepatic hemoprotein turnover

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There are (X) number of chemically (equivalent/variable) bridge carbons in heme molecule. Cleavage occurs at which one(s)?

X = 4;
Variable;

Only at alpha bridge carbon

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Bruise: turns blue/purple to greenish due to...

Action of heme oxygenase on heme, forming biliverdin (green)

Heme oxygenase is an important enzyme in (X) process. It (uses/produces) (NADP/NADPH) and molecular oxygen to form (Y).

X = heme catabolism Uses; NADPH Y = Biliverdin

Heme catabolism: the green-blue (X) compound is (slowly/quickly) converted to (Y). Which enzyme carries this out?

X = biliverdin Quickly (almost immediately); Y = bilirubin (yellow-orange); Biliverdin reductase

Both step 1 and step 2 of heme catabolism (require/produce) which electron carrier?

Require; NADPH

(X) enzyme of heme (biosynthesis/catabolism) carries out reaction that produces CO.

X = heme oxygenase; | Catabolism (first step)

Conjugation of BR: (1/2/4) molecules of (X) donate glucuronic acid and (Y) enzyme adds them to BR.

2; X = UDP-glucuronic acid Y = BR Glucuronyl Transferase

Heme: the "AP AP AP PA" orientation of (X) compound will eventually depict symmetry down the line in (Y) molecule.

``` X = uro'gen; Y = BRDG ```

In which cell types would you find heme oxygenase?

1. Phagocytes in spleen 2. Kupffer cells 3. Tissue macrophages

Heme catabolism: The OATP transporter transports (X) into (Y).

``` X = BR Y = hepatocyte (from blood) ```

Heme catabolism: The ABCC-2 transporter transports (X) into (Y).

``` X = BRDG Y = Bile (from hepatocyte) ```

T/F: Once conjugated to BRDG and secreted into bile, the compound doesn't become BR again.

False - sugars come off via gut flora of large intestine

BRDG in bile reaches (X) part of gut, where it becomes (Y), then (Z).

``` X = large intestine; Y = BR Z = Urobilinogen ```

Urobilinogen is formed in (X) location from (BR/BRDG). Most of it has which fate?

X = large intestine; BR 90% becomes stercobilin (brown) and excreted in feces

A small portion, (X)%, of urobilinogen has which fate?

X = 10 Enters enterohepatic circulation and filtered/secreted as urobilin/urobilinogen via kidney

Normal total BR conc in blood.

under 1 mg/dL

Normal (conjugated/unconjugated) BR-Alb conc in blood.

Unconjugated; | 0.4 mg/dL

Normal BRDG conc in blood.

0.1 mg/dL

T/F: There is absolutely no BRDG in blood since it's conjugated and directly secreted into bile.

False - always a small, constant amount (0.1 mg/dL) leaking back via sinusoids into blood

Urine normally contains (little/no) urobilinogen, (little/no) BRDG, and (little/no) BR.

Little; No (at least not detectable); No

In state of hemolysis (massive RBC lysis), how will urine values of Urobilinogen/BRDG/BR differ from normal?

Significant increase in Urobilinogen; No change in BRDG; NO BR IN URINE!!

Decrease in BR uptake by hepatocyte indicates that (X) transporter is defective. How will this effect urine values of UroB/BRDG/BR?

X = OATP; Less than normal UroB; No change in BRDG; NO BR IN URINE!!

T/F: Severe defect in BR Conjugation is incompatible with life.

True

Gilbert's Syndrome: mutation is in (X) region of (Y) gene. What are typical symptoms?

``` X = promoter Y = BRGT (BR glucuronyl transferase) ``` Usually asymptomatic

Crigler-Najjar Type I: mutation in (X) region of (Y) gene. The protein responsible for (Z) is (absent/reduced/overproduced).

``` X = coding Y = BRGT (BR glucuronyl transferase) Z = BR Conjugation ``` Absent (FATAL)

Crigler-Najjar Type II: mutation in (X) region of (Y) gene. The protein responsible for (Z) is (absent/reduced/overproduced).

``` X = coding Y = BRGT (BR glucuronyl transferase) Z = BR Conjugation ``` Reduced levels

A patient with Gilbert's Syndrome will have which urine values of UroB/BRDG/BR?

All absent

Dublin-Johnson disease: (X) protein is defective, thus resulting in defective (absorption/secretion) of (Y).

X = ABCC-2 transporter Secretion; Y = BRDG (into bile)

A patient with Dublin-Johnson disease will have which urine values of UroB/BRDG/BR?

Less than normal UroB; | Very high BRDG (can't exit into bile and become stercobilin, so refluxes back to blood and filtered via kidney)

Your patient has prominent orange-color to their urine. What do you expect is going on? Which color will their stool likely be?

Impaired post-hepatic transport of BRDG (into bile), so high levels in urine (Dublin-Johnson Disease); Stool likely very pale/grey

Bile Duct Stone/obstruction will likely have similar urine values of UroB/BRDG/BR as (X) disease/state. What's the key difference between these two scenarios?

X = Dublin-Johnson disease (post-hepatic transport impairment); Bile Duct obstruction causes severe pain

In the intestine, one mole of BRDG is hydrolyzed to one mole of (X) and 2 moles of (Y) by (Z) enzyme.

``` X = BR Y = Glucaronic acid Z = beta-glucuronidase ```

Before birth, BR is cleared in fetus via (X).

X = maternal circulation

T/F: Neonatal jaundice affects most infants.

True - though to various extents

Neonatal jaundice: the underlying cause is (high/low) expression of (X) enzyme.

Low; | X = BR Glucaronyl Transferase

Neonatal jaundice: UV light therapy works via which mechanism?

Cleaves BR into non-toxic products

Neonatal jaundice: (X) accumulation is toxic to (Y) system (kernicterus) since (Z) formation is incomplete.

``` X = BR Y = nervous Z = BBB ```

Porphyrias can be classified according to location of defective enzyme. What are these classifications? Star the most common.

1. Hepatic* | 2. Erythropoetic (bone marrow)

(Hepatic/Erythropoetic) porphyrias are usually adult onset and always inherited in (AD/AR/sex-linked) manner. Thus, heterozygotes have (no/some) functional enzyme.

Hepatic; AD; Some (50%)

AIP (Acute Intermittent Porphyria) is (Hepatic/Erythropoetic) and defined by (X) enzyme deficiency.

Hepatic; | X = PBG Deaminase

PCT (Porphyria Cutanea Tarda) is (Hepatic/Erythropoetic) and defined by (X) enzyme deficiency.

Hepatic; | X = Uro'gen III Decarboxylase

VP (Variegate Porphyria) is (Hepatic/Erythropoetic) and defined by (X) enzyme deficiency.

Hepatic; | X = Proto'gen IX DH

T/F: All hepatic porphyrias are photo-sensitive.

False - not AIP

Photosensitive porphyrias, such as (X), means that (Y) occurs when patient exposed to (Z).

``` X = PCT, VP Y = blistering lesions on skin (due to free radicals) Z = light ```

The underlying issue with porphyrias is too (much/little) (X) means (over/under)-stimulated (Y).

Little; X = heme (produced) Over-stimulated Y = ALA Synthase (no feedback inhibition; buildup of intermediates)

T/F: Normally, heterozygotes with porphyria have enough enzyme to be asymptomatic.

True - enough heme produced to shut off ALAS

Certain factors, such as (X), can precipitate crisis in porphyria by (increasing/decreasing) (Y).

X = drugs, hormones, starvation, EtOH Increasing; Y = hepatic heme utilization (to make cytochrome p450)

(X) intermediate in heme biosynthesis is directly neurotoxic and causes (Y) symptom in porphyria crisis.

``` X = ALA Y = confusion ```

HC (Hered Coproporphyria) is (Hepatic/Erythropoetic) and defined by (X) enzyme deficiency.

Hepatic; | X = Copro'gen decarboxylase

In (X) porphyria(s), you'd expect buildup of ALA, PBG, and o'gens.

X = HC (Hered Coproporphyria) and VP

Treatment for acute porphyrias:

IV Heme

Which tests would you conduct to test for porphyrias?

1. Genetic | 2. Urine/stool

Urine analysis to test for porphyrias. What are you looking for?

Intermediates (ALA to Copro'gen)

Stool analysis to test for porphyrias. What are you looking for?

Intermediates that are more hydrophobic (Copro'gen or Proto'gens)

Acute porphyrias differ from chronic in that:

Asymptomatic until precipitating event causes symptoms (vomiting, pain, confusion)

In chronic hepatitis (X) infection, sever liver inflammation can ensue. This has been tied with (Y) porphyria.

``` X = C Y = PCT ```

In most patients with PCT (porphyria cutanea tarda), (X) enzyme dysfunction is (acquired/inherited).

X = uro'gen III DC | Acquired (i.e. HCV) - 80% of cases

A patient with chronic HCV comes into your clinic with rashes/skin lesions. You suspect that he has (X) porphyria and, further, that (Y)% max of (Z) enzyme is functional.

``` X = PCT Y = 25 Z = uro'gen III DC ```

The underlying reason that HCV as well as (X) conditions cause PCT is:

X = HIV/alcohol use Liver inflammation and Fe overload (leads to oxidative stress)

Chronic HCV: (X) overload in liver can cause oxidative stress. This causes (Y) production, which (stimulates/inhibits) (Z).

X = Fe Y = uroporphomethane (via uro'gen oxidation) Inhibits Z = uro'gen III DC (thus, PCT ensues)

The rash/blisters in your patient with HCV and PCT came from (X), which came from sunlight reacting with (Y), which actually came from (Z).

``` X = ROS Y = porphyrins Z = o'gen oxidation (oxidative stress in liver) ```

(X) environmental exposure inhibits which two enzymes in heme biosynthesis?

X = lead 1. ALA dehydratase 2. Ferrochelatase

Never give pt with acute intermittent porphyria (X) drugs

X = barbiturates

Most common porphyria:

PCT