Heme Synthesis And Breakdown Flashcards
Describe the structure of hemoglobin
*made of 4 heme
1 heme= 1 porphyrin ring—>4 pyrolle—> 1 ferrous iron
What state is iron in in Hb?
Ferrous
2+ state
*oxidation to Fe3+ (ferric) inactivates hb
What structures are heme present in?
Hemoglobin
Myoglobin
Cytochromes
They are three phases of heme synthesis, where do they take place?
P I and III - mitochondria
P II - cytosol
What parts of the body does most heme synthesis occur
Liver and bone marrow
Defect in one or more stages of heme synthesis can cause
Porphyrias (lots of porphyrin)
Basic outline of Phase 1 of heme synthesis
Reactants:
- Glycine
- Succinyl co A
Products:
ALA
Basic outline of heme synthesis phase 2
2 ALA —> porphobilinogen
4 porphobilinogen—>tetrapyrole ring of coproporphyrinogen III
*MAKES PORPHYRIN RING
Basic outline of heme synthesis stage 4
Coproporphyrinogen III—> protoporphyrinogen IX —> protoporphryin IX —> add Fe2+ —> heme
What coenzyme is needed in Phase 1 of heme synthesis for ALA synthase
Vitamin B6 (PLP)
Why does B6 deficiency cause anemia
Because ALA synthase needs it to make heme
*no heme = anemia
What are the 2 isoforms of ALA
ALAS 1 (everywhere)
ALAS 2 (in bone marrow only) -has an iron response element in mRNA
- INHIBITED BY HEME and HEMIN
- ACTIVATED BY IRON
What activates and inhibits ALA synthase
Inhibited by HEME / HEMIN
Activated transcription by IRON
What two enzymes does lead inactivate
ALA dehydratase ( makes PBG) *has zinc
Ferrochelatase (adds iron)
*has Fe
[accumulation of ALA and protoporphyin IX ]
What three impacts on the body’s healthy does lead poisoning have ?
- Neurological affects
(ALA resembles GABA) - Anemia
(Bc no heme) - Impacts energy production
(Affects cytochromes heme)
*fatigue
What is the Greek definition of porphyrias
Purple pigment
What is the general defect in porphyria
*inherited metabolic disorder
DEFECT IN HEME SYNTHESIS
- acute hepatic = Neuro problems
- erythropoietic = photosensitivity
Acute intermittent porphyria is related to what enzyme defect? Where?
Porphobilinogen deaminase
(PBG—> hydroxymethybilane)
**HEPATIC
Congenital erythropoietic porphyria is related to what enzyme defect? Where?
Uroporphyrinogen III cosynthase
(Hydroxymethylbilane —> uroporphyrinogen III)
- erythropoietic
porphyria cutaneous Tarda is related to what enzyme defect? Where?
*MOST COMMON IN US
Uroporphyrinogen decarboxylase
(Uroporphyrinogen III —> coproporphyrinogen III)
*LIVER AND erythropoietic
Variegate porphyria is related to what enzyme defect? Where?
*celebrites
Protoporphryinogen oxidase
(Protophyrinogen IX —> protoporphrin IX)
*HEPATIC
In congenital erythropoietic porphryia, there is a build up of _______ , which oxidizes into _____. This causes what symptoms ?
Uroporphyrinogen I
Uroporphyrin I (not a heme intermediate)
- red urine
- red teeth
- skin photosensitivity
What system handles hemoglobin degradation
Reticulo-endothelial system
- globin breaks —> amino acids
- heme removed for degradation
Heme is broken into biliverdin by what enzyme
Heme oxygenase
[needs oxygen]
*porphryrin ring —> tetrapyrrole rings
What is released during heme degradation by heme oxygenase
Carbon monoxide
During heme degradation, what happens to iron
Iron IX oxidized
Ferrous—>ferric
2+—> 3+
What enzyme converts biliverdin to bilirubin?
Biliverdin reductase
-removes double bonds
*uses NADPH
What binds to free unconjugated (insoluble) bilirubin when it is first released into the bloodstream?
Albumin
The bilirubin-albumin complex is made and transported where so that bilirubin can be conjugated
The liver
In the liver (hepatocytes), bilirubin is conjugated with ________ to make it double
Glucuuronic acid
UnConjugated/free/indirect bilirubin vs conjugated/direct bilirubin
Newly released bilirubin is insoluble and is unconjugated
Bilirubin + glucuronic acid = is soluble and is conjugated
What is the general outline of bilirubin conjugation in the liver
- Glucose is made into UDP-glucouronate
2. UDP-glucuronate + BR conjugated (by BR-UDP glucuronyl transferase) to make BR-monogluconide
What is the RLS of bilirubin blood removal
BR-monoglucuronide to diuronide
Defect in what enezyme of bilirubin conjugation gives rise to many jaundiced
Bilirubin-UDP glucuronyltransferase
What are the colors associated with heme, biliverdin, and bilirubin
Purple
Green
Red-orange
Conjugated bilirubin is then sent where to be stored until use ?
Stored in the gallbladder as bile
Explain what happens to conjugated bilirubin (BR-diglucuronide) after it leaves the gallbladder
- Converted to free bilirubin
- —> urobilinogen
- Sent to kidneys (reabsorbed) or sent to colon (not reabsorbed)
What happened when urobilinogen is sent to the colon? Kidneys?
And what is the associated colors?
Colon:
—> stercobilin —>feces
Kidney:
—>urobilin —> urine
- urobilnogen is colorless
- stercobilin is brown
- urobilin is yellow
Jaundice is also known as
Hyperbilirubinemia
*elevated blood bilirubin
Imbalance of production and excretion
What are the 3 types of Juandice
- Pre-hepatic
- Intracellular-hepatic
- Post-hepatic
Causes of pre-hepatic juandice
*increased unconjugated bilirubin production
(Also: hemolytic anemia’s, hemorrhage, liver cant conjugate bilirubin, G6P dehydrogenase deficiency, imcompability of maternal-fetal blood )
What are pre-hepatic jaundice findings
*elevated unconjugated bilirubin
- normal conjugated BR blood levels
- normal ALT/AST
- normal urine
Causes if intra-hepatic jaundice
- impaired hepatic uptake (faulty transporter)
- impaired conjugation
- impaird secretion of conjugated BR
Or hepatic dysfunction from CRIGGLER-NAJJAR SYNDROME or GILBERT SYNDROME
Intra-hepatic jaundice findings
- increased ALT/AST
- conjugated-BR in urine
- variable direct/indirect BR in blood
- urobilinogen urine normal
What causes post hepatic jaundice (cholestatic jaundice or cholestasis)
*problem with indirect bilirubin excretion
From obstruction: gall stones, tumors, drugs,….
Post-hepatic jaundice findings
- elevated conjugated BR
*conjugated BR in urine
*no urine urobilinogen
DARK URINE, PALE STOOL
-normal AST/ALT
What is the cause of neonatal (physiological) jaundice
- elevated unconjugated BR
- immature hepatic metabolic pathway cant conjugate
- UDP-GT enzyme deficiency
What is phototherapy?
- treatment for neonatal juandice
- blue fluorescent light makes Bilirubin more soluble
Besides phototherapy, what is another way to treat physiological juandice? (Not pathological)
-intramuscular injection of tinmesoporphyrin which inhibits heme oxygenase therefore stopping bilirubin production
TINMESOPORPHYRIN INJECTION
What are the three UDP-GT related disorders? (Converts indirect bilirubin —>direct)
Crigler-Najjar syndrome I
Crigler-Najjar syndrome II
Gilbert syndrome
- complete absence of UDP-GT gene
- no bilirubin conjugation
- SEVERE HYPERBILIRUBINEMIA (jaundice)
Criggler-Najjar Syndrome Type 1
What happens if babies develop Criggler-Najjar syndrome type 1
- indirect bilirubin accumulates in brain
- causes KERNICTURUS encephalopathy and brain damage
What are the treatment options for Crigler-Najjar syndrome type 1
Blood transfusion Phototherapy Heme oxygenase inhibitors Oral calcium phosphate/carbonate LIVER TRANSPLANT
What does oral calcium phosphate/carbonate do in relation to bilirubin
Forms a complex with bilirubin in the the gut
- mutation in UDP-GT gene
- decreased activity of conjugated BR formation
Criggler-Najjar syndrome type 2
- reduced UDP-GT activity
- common, benign disorder
- elevated issues with fasting, stress, or alcohol
Gilbert syndrome
In hepatitis (liver inflammation) the liver dysfunction (from many different causes) has what affect on bilirubin? Therefore what effect on the body?
-increased levels of indirect/direct bilirubin in blood
- skin and sclera become yellow
- urine becomes dark
Color changes in brushing:
Heme(red/purple)—>biliverdin(green) —> bilirubin (orange)—> hemosiderin (brown)
