Heme

Question 1

Porphyria

Answer 1

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

Question 2

Heme synthesis general

Answer 2

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

Question 3

Heme synthesis regulation

Answer 3

Heme itself inhibits the ALA synthase reaction (mitochondria)

Rate limiting step

Question 4

Lead poisoning

Answer 4

Inhibits the 2nd (cytosol) and last reaction (mitochondria) of heme synthesis

Ferrochelatase and ALA dehydratase

Protoporphyrin and ALA accumulate in urine

Question 5

Acute intermittent porphyria

Answer 5

Hepatic

Enzyme: hydroxymethylbilase synthase

Porphobilinogen and delta-aminolevulinic acid accumulate in urine

Urine darkens on exposure to light and air

NOT photosensitive

Question 6

Congenital erythropoietic porphyria

Answer 6

Enzyme: uroporphyrinogen III synthase

Uroporphyringoen I and coproporphyrinogen I accumulate in urine

Photosensitive

Question 7

Porphyria cutanea tarda

Answer 7

Most common

Both hepatic and eryhropoetic

Uroporphyringoen decarboxylase

Uroporphyrin accumulates in urine

Photosensitive

Question 8

Hereditary coproporphyria

Answer 8

Hepatic

Coproporphyrinogen oxidase

Copro…III and other intermediates prior to the block accumulate in urine

Photosensitive

Question 9

Variegate porphyria

Answer 9

Hepatic

Protoporphyrinogen oxidase

Protoporphyrinogen IX

Photosensitive

Question 10

Erythropoietic protoporphyria

Answer 10

Ferrchelatase

Protoporphyrin accumulates in eryhrocytes, bone marrow, and plasma

Photosensitive

Question 11

Major source for the breakdown of heme is from

Answer 11

Senescent RBCs

Cells are engulfed by macrophages of teh reticuloendothelial system

Where the heme is broken down to unconjugated bilirubin (B)

Question 12

Fat of bilirubin in heme breakdown pathway

Answer 12

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

Question 13

BG is secreted through…

Answer 13

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

Question 14

What gives urine its yellow color

Answer 14

Urobilinogen

Question 15

No reabsorbed urobilinogen

Answer 15

Oxidized by intestinal floral to stercobilin and excreted in the feces

Gives feces its brown color

Question 16

High levels of bilirubin in blood =

Answer 16

Jaundice

Question 17

Massive lysis of RBCs (like sickle cell anemia, pyruvate kinase or G6P DH deficiency)

Answer 17

May produce bilirubin faster than it can by conjugated by the liver…

Question 18

Hemolytic jaundice

Answer 18

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

Question 19

Obstructive jaundice

Answer 19

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

Question 20

Hepatocellular jaundice

Answer 20

Damage to liver cells (cirrhosis)

Decreased conjugation

B and U levels in blood are elevated

AST and ALT levels are elevated

Question 21

Newborn jaundice

Answer 21

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

Question 22

Creatine phosphate

Answer 22

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

Question 23

Making creatine

Answer 23

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

Question 24

Creatinine

Answer 24

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