George III Mary, Queen of Scot Attempted murder of Elizabeth I Executed 1587 James I Intermittent Porphyria Purple Urine George I (great grandfather) - 67 George II (grandfather) - 77 Frederick (father) - 44 George III - 82 * * *

What’s Wrong with George III Cholic Chest pains Stomach cramps Constipation Tachycardia Profuse sweating Gibberish speech Joint swelling Loss of taste Irritability Hallucinations Delusions Delirium Purple Urine Porphyria 6 different disorders 6 enzymes  -aminolevulinate related

COO - CH 2 C=O S-CoA CH 2 COO - NH CO 2 +HS-CoA COO - CH 2 C=O CH 2 NH 2  -Amino levulinate Succinyl-CoA Glycine Porphyrin Biosynthesis Step 1: Synthesis of  -Aminolevulinate (  -ALA)

COO - CH 2 C=O CH 2 NH 2 COO - CH 2 C=O CH 2 NH 2 COO - CH 2 C C NH 2 N C C COO - CH 2 H H Porphobilinogen -2H 2 O This is the basic building block Step 2: Synthesis of the basic ring unit

COO - CH 2 C C NH 2 N C C COO - CH 2 H H COO - CH 2 C C NH 2 N C C COO - CH 2 H H COO - CH 2 C C NH 2 N C C COO - CH 2 H H Ring Closure Step 3: 4 NH 4 + Porphobilinogen deaminase Intermittent porphyria of George III

I II III IV Key Ring in synthesis

P N H N AP H A P N H N A P H Uroporphyrinogen III A I II III IV Inverted C CC C Uroporphyrinogen III Cosynthase Uroporphyrinogen I Synthase +

P N H N AP H A P N H N A P H A I II III IV C CC C N N AP H A P N H N A P H P I II III IV C CC C A H Uroporphyrinogen IIIUroporphyrinogen I Non-Symmetrical Symmetrical

P N H N AP H A P N H N A P H A I II III IV C CC C P N H N MP H M P N H N M P H M I II III IV C CC C Coproporphyrinogen III 4 CO 2 COO - CH 2 C C N C C COO - CH 2 H H CH 3 C C CH 2 N C C COO - CH 2 H H

P N H N MP H M P N H N M P H M I II III IV C CC C P N H N MV H M V N H N M P H M I II III IV C CC C 2 CO 2 Protoporphyrinogen IX CH 3 C C CH 2 N C C COO - CH 2 H H CH 3 C C CH 2 N C C CH H H

P N H N MV H M V N H N M P H M I II III IV C CC C P N H N MV H M V N H N M P H M I II III IV C CC C Conjugated Double bonds

P N H N MV H M V N H N M P H M I II III IV C CC C Fe 2+ Ferrochetalase HEME Iron is added as Fe 2+

Breakdown Heme N O N NN O PMMMVVPM N O N NN O PMMMVVPM IV Billiverdin Billirubin BloodLiver (Albumin)