Heme sythesis Functions hemoglobin cytochrome b4 P450 Location of synthesis involves both the mitochondria and the cytosol occurs in nearly every cell occurs in RBC progenitor cells CANNOT occur in RBCs because they lack mitochondria Pathway ALA synthase is rate limiting enzyme (see above) Deficiencies in heme synthesis hemin occurs when Fe3+ is incorporated instead of Fe2+ porphyria causes symptoms due toxic accumulation of pathway intermediates aminolevulinic acid (ALA) causes neurological symptoms protoporphyrins cause photosensitivity conjugated structure what absorbs light energy and forms free radicals symptoms worsened by sunlight P450 inducing drugs stimulate the heme synthesis pathway to ↑ production ex.) barbiturates, alcohol treatment limit exposure to sun and P450 inducing substances hemin inhibits new heme production types porphyria cutanea tarda deficiency in uroporphyrinogen decarboxylase AD late onset (4th or 5th decade) symptoms often noticed with alcohol consumption presentation photosensitivity hyperpigmentation body's attempt to protect the skin dark red/brown colored urine acute intermittent porphyria deficiency in porphobilinogen deaminase AD late onset presentation NO photosensitivity episodic psychological symptoms (paranoia, anxiety, depression) vague abdominal pain patients can present with a history of laparoscopies dark red/brown colored urine ALA and porphobilinogen (PBG) present in urine during symptoms poisoning lead induced deficiency in ALA dehydratase and ferrochelatase both enzymes are Zn2+ dependent metalloenzymes Pb2+ replaces the Zn2+ at the active site presentation ↓ in IQ microcytic anemia with coarse basophilic stippling abdominal pain ↑ in ALA without ↑ in PBG differentiates from porphyrias lead lines in bone and teeth xrays nephrotoxicity deposition in nuclei of proximal renal tubular cells hexachlorobenzene induced deficiency in uroporphyrinogen decarboxylase presentation hypertrichosis (↑ body hair coverage) found in (now banned in USA) pesticides iron deficiency iron incorporated in the final step result is microcytic hypochromic anemia see Trace metals topic vitamin B6 deficiency rate limiting enzyme (ALA synthase) requires most commonly due to isoniazid therapy see Vitamins topic Degradation of Heme Function rid body of hemoglobin removed from degraded RBCs Location of degradation spleen site of RBC destruction liver site of bilirubin conjugation intestine conversion by normal gut flora Pathway Bilirubin Properties insoluble must travel in blood bound to albumin conjugation direct (conjugated) glucuronate group added soluble indirect (unconjugated) glucuronate group not yet added insoluble Modified forms urobilinogen gives urine yellow color stercobilin gives feces brown color with a blocked bile duct no stercobilin in feces and it is clay colored