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CPR Test 2 > Heme Biochem > Flashcards

Heme Biochem Flashcards

1
Q

what are the key features of hemoglobin and heme

A

Hemoglobin has 4 globular sub units that are each bound to an iron containing a heme

heme has a heterocyclic porphyrin ring with an iron present in center

key features of a porphyrin ring:

  • have 4 5-membered rings containing nitrogen connected by single carbon bridges
  • iron present in ferrous state (Fe2+)
  • oxidation to ferric state inactivates hemoglobin
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2
Q

where does biosynthesis of Heme occur?

A

occurs in liver and erythroid cells of bone marrow

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3
Q

what are the 3 phases of biosynthesis of Heme

A

Phase 1: in mitochondria, synthesis of delta-aminolevulinic acid (ALA) from glycine and succinyl coenzyme A

Phase II: In cystol, condensation of two delta-ALAs to form porphobilinogen (PB), condensation of four PBs to assemble the tetrapyrrole ring system of coproporphyrinogen III

Phase III: in mitochondria, two oxidation reactions of coproporphyrinogen III to install the side chain vinyl groups in protoporphyrinogen IX and generate the fully conjugated ring system of protoporphyrin IX insertion of Fe2+ by ferrochelatase

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4
Q

what happens if their is a defect in any phase of the making of heme?

A

a defect in one or more stages of heme synthesis causes porphyrias

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5
Q

important enzymes in each of the three phases of heme production

A

Phase 1: ALA synthase (need vitamin B6)
-generation of ALA

Phase II: ALA dehydrase
-Generation of Coproporphyrinogen III

Phase III: ferrochelatase
-generation of protoporphyrin and introduction of iron to form heme

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6
Q

what is required by ALA synthase to make ALA?

A

B6 (pyroxidal phosphate)

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7
Q

what happens in lead poisoning

A

Lead can inactivate 2 important enzymes in the heme synthesis

Ala dehydratase (contains Zn)
Ferrochelatase (contains Fe)

leads to both ALA and Protoporphyrin IX accumulation

causes anemia (microcytic and hypochromic)

impacts ATP synthesis and energy metabolism

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8
Q

how does production of Heme affect the heme biosynthesis pathway

A

Heme acts as a negative feeback inhibiting ALA synthase

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9
Q

what are Porphyrias?

A

inhereted metabolic disorders
-defect in heme synthesis

Acute Hepatic: neurological symptoms

Erythropoietic: affect skin, photosensitivity

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10
Q

Acute intermittent porphyria

A

PBG demainase (in liver)

Autosomal dominant
deficiency leads to excessive production of ALA and PBG
-Periodic attacks of abdominal pain and neurological dysfunction

Hepatic

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11
Q

Congenital erythropoietic porphyria

A

Uroporphyrinogen III synthase (in erythrocytes)

autosomal recessive
accumulation of uroporphyrinogen I and its red-colored, air oxidation product uroporphyrin I
Photosensitivity, red color in urine and teeth
hemolytic anemia

Erythropoietic

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12
Q

Porphyria cutanea tarda (PCT)

A

Uroporphyrinogen decarboxylase

autosomal dominant
accumulation of uroporphyrinogen III converting to uroporphyrinogen I and its uroporphyrin oxidation products
most common in US
photosensitivity resulting in vesicles and bullae on skin of exposed area, wine red colored urine

Hepatoerythropoietic

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13
Q

Variegate porphyria

A

Protoporphyrinogen IX oxidase

autosomal dominant
Photosensitivity and neurologic symptoms and developmental delay in children

Hepatic

also called Celebrity porphyrias
-KIng george III had it

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14
Q

how is heme degraded and what is it broken down too

A

handled by the reticulo-endothelial system
-degrades hemoglobin to globin and heme

globin broken down to amino acids
heme processed for degradation

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15
Q

what is difference between heme and bilirubin

A

heme is the porphyrin ring

bilirubin is a cut in the corner and flattened out making a tetrapyrrole rings and has no Iron

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16
Q

step by step of heme degradation

A

Heme oxygenase removes the bridge between pyrrole rings

  • requires oxygen
  • carbon monoxide released

Iron oxidized from ferrous to ferric

Biliverdin synthesized

Biliverden reduced to bilirubin by enzyme biliverdin reductase
-requires NADPH

17
Q

Conjugation of Bilirubin

A

Bilirubin is released in BLood stream and is very hydrophobic
-Free/uncongugated/indirect BR is insoluable so will bind to albumin

will then get picked up by liver and get conjugated with glucuronic acid making it soluble (conjugated/direct BR)

  • glocose converted toe UDP-glucose then converted to UDP-glucuronic acid
  • UDP glucuronyl transferase will put the gluconic acid on to BR to mono and then diglucuronide
  • UDP glucuronyl transferase is the rate limiting step
18
Q

where does the bilirubin-diglucuronide go after being made in liver

A

goes straight into the gall bladder then will go into small intestine where it gets converted to bilirubin via microbial reduction

then in large intestine it will turn to Uroblinogen where it will go into the kidney and be converted to urobilin (color of urine)

also will stay in large intestine and go to colon where it turns to stercobilin and that is what makes the feces brown

19
Q

what is jaundice

A

aka Hyperbilirubinemia

Elevated levels or BR in blood stream
-Imbalance between production and excertion of bilirubin

20
Q

Pre-hepatic Jaundice

A

Increased production of unconjugated BR

  • excess hemolysis (hemolytic anemia)
  • glucose 6-PO4 dehydrogenase deficiency
  • internal hemorrhage
  • Problems with incompatibility of maternal-fetal blood groups
  • Capacity of liver to uptake exceeded
elevated levels of unconjugated/indirect BR
-normal conjugated BR
normal ALT
-normal ASL
-Urobilinogen present in urine
21
Q

Intra-Hepatic Jaundice

A

Impaired hepatic uptake, conjugation, or secretion of conjugated BR

  • generalized liver dysfunction
  • liver cirrhosis
  • viral hepatitis
  • Criggler-najjar syndrome
  • gilbert syndrome

variable increases in unconjugated and conjugated BR depending if pre and post

increased ALT and AST

Urobilinogen levels are normal

22
Q

Post hepatic Jaundice

A

AKA cholestatic jaundice or cholestasis (decreased bile flow)

Problems with BR excretion

  • cholangiocarcinoma
  • gall stones
  • obstruction of biliary drainage
  • infiltrative liver disease
  • drugs (anabolic hormones, chlorpromazine, phenytoin)
  • lesions

elevated Blood levels of conjugated BR

  • normal AST and ALT
  • Elevated alkaline phosphatase (ALP)
  • conjugated BR is present in urine (dark)
  • no urobilinogen in urine
  • no stercobilin in feces
23
Q

Neonatal jaundice

A

many newborns develop jaundice due to elevation of uconjugated bilirubin
-called physiological jaundice

Immature hepatic metabolic pathways unable to conjugate and excrete bilirubin

deficiency of UDP-GT enzyme

breakdown of fetal hemoglobin as it is replaced with adult hemoglobin

accumulation of excess BR in blood

premature birth aggravates this situation

24
Q

Phototherapy

A

used to treat jaundiced newborns

when exposed to blue florescent light, BR undergoes photo-conversion to form more soluble isoforms

or intramuscular injection of tin-mesoporphyrin which is a strong inhibitor of heme oxygenase to prevent heme breakdown to form bilirubin

25
Q

Criggler-Najjar syndrome

A

severe hyperbilirubinemia
results from deficiency of UDP-GT

BR accumulates in babies brain
can cause brain damage and encephalopathy (kernicturus)

therapy: blood transfusions
phototherapy
heme oxygenase inhibitors
oral calcium phosphate and carbonate
liver transplantation

type II is much less severe, benign form

26
Q

Gilbert syndrome

A

reduced activity of UDP-GT (25 percent)

relatively common

increased may show more with fasting, stress, alchol

27
Q

Hepatitis

A

Inflammation of the liver leading to liver dysfunction

causes viral (A, B,C) alcoholic cirrhosis, liver cancer

increased levles of unconjugated and conjugated BR in blood

caused skin and sclera yellow discoloration due to accumulation

dark tea colored urine

28
Q

Biochemistry of brusies

A 
red = heme
green = biliverdin
orange: bilirubin
hemosiderin = brown
blue = hemoglobin

as it heals gets yellow and then skin color

CPR Test 2 (25 decks)

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