Heme Flashcards
Porphyria
Group of rare inherited disorders caused by enzyme deficiencies in heme biosynthesis
Usually no symptoms in heterozygous
Many steps in heme making…each type has a specific build up of substrate and toxic to the nervous system
Cutanea tarda = most common
Build up of urophorphyrinogen I —> reacts with molecular O2 to form dangerous radicals taht can severely damage the skin
Individuals photosensitive and increase in facial heir….urine can be bright red
Heme synthesis general
Begins with the condensation of succinyl-CoA and Glycine within the mitochondria to form ALA
Enzyme: ALA synthase
= the rate limiting step
ALA then moves to cytosol —> several reactions…
Then back to mitochondria for final 3 reactions
Heme synthesis regulation
Heme itself inhibits the ALA synthase reaction (mitochondria)
Rate limiting step
Lead poisoning
Inhibits the 2nd (cytosol) and last reaction (mitochondria) of heme synthesis
Ferrochelatase and ALA dehydratase
Protoporphyrin and ALA accumulate in urine
Acute intermittent porphyria
Hepatic
Enzyme: hydroxymethylbilase synthase
Porphobilinogen and delta-aminolevulinic acid accumulate in urine
Urine darkens on exposure to light and air
NOT photosensitive
Congenital erythropoietic porphyria
Enzyme: uroporphyrinogen III synthase
Uroporphyringoen I and coproporphyrinogen I accumulate in urine
Photosensitive
Porphyria cutanea tarda
Most common
Both hepatic and eryhropoetic
Uroporphyringoen decarboxylase
Uroporphyrin accumulates in urine
Photosensitive
Hereditary coproporphyria
Hepatic
Coproporphyrinogen oxidase
Copro…III and other intermediates prior to the block accumulate in urine
Photosensitive
Variegate porphyria
Hepatic
Protoporphyrinogen oxidase
Protoporphyrinogen IX
Photosensitive
Erythropoietic protoporphyria
Ferrchelatase
Protoporphyrin accumulates in eryhrocytes, bone marrow, and plasma
Photosensitive
Major source for the breakdown of heme is from
Senescent RBCs
Cells are engulfed by macrophages of teh reticuloendothelial system
Where the heme is broken down to unconjugated bilirubin (B)
Fat of bilirubin in heme breakdown pathway
Can be also be transported in the blood associated with albumin
In the liver, unconjugated B is conjugated to glucuronic acid to form B diglucoronide (BG)
Bilirubin glucoronyltransferase
BG is secreted through…
The bile duct into the intestines
The intestinal flora deconjugates the BG and converts bilirubin —> urobilinogen (U)
Some of this is reabsorbed by the gut…enters the portal blood and may participate in enterohepatic urobilinogen circulation
The remainder of the reabsorbed U is converted to urobilin in the kidneys and excreted in the urine
What gives urine its yellow color
Urobilinogen
No reabsorbed urobilinogen
Oxidized by intestinal floral to stercobilin and excreted in the feces
Gives feces its brown color
High levels of bilirubin in blood =
Jaundice
Massive lysis of RBCs (like sickle cell anemia, pyruvate kinase or G6P DH deficiency)
May produce bilirubin faster than it can by conjugated by the liver…
Hemolytic jaundice
Liver cannot respond fast enough to the increased RBC turnover in conjugating this excess bilirubin
Conjugated bilirubin and subsequent Urobilinogen may be high
But unconjugated bilirubin in blood will definitely be high —> jaundice symptoms
Obstructive jaundice
Obstruction of bile duct
Stools are pale clay color and urine that darkens upon stading
Liver regurgitates conjugated bilirubin into blood and its eventually excreted in the urine
Hepatocellular jaundice
Damage to liver cells (cirrhosis)
Decreased conjugation
B and U levels in blood are elevated
AST and ALT levels are elevated
Newborn jaundice
Premature infants
Activity of heptic bilirubin glucoronyltransferase is low at birth
Elevated B can diffuse into the basal ganglia and cause toxic encephalopathyt
Treated with blue fluorescent light —> makes B more water soluble…can be excreted into bile with unconjugation
Creatine phosphate
High energy compound found in muscle that can reversible couple the energy from the hydrolysis of the phosphate group to make ATP
Provides a small buy rapidly mobnilized reserve of high energy phopshates that can be used to maintain IC level of ATP during first few minutes of intense muscular contraction
Amount of it is proportional to muscle mass
Making creatine
From glycine, arginine and the methyl group donated from SAM
Creatine —> creatine - P by creatine kinase
Using ATP as a donor
Plasma creatine kinase = muscle damage
Creatinine
Creatine adn creatine P
Spontaneously cuclize at a slow but constant rate to form creatinine
Which is excreted in urine
Amount of creatinine excreted is proportional to levels of creatine phopshate in body…thus can estimate muscle mass
Rise in creatinine blood = kidny malfunction because creatinine normally is rapdily removed from the blood and excreted in urine
