Heme Synthesis Flashcards
Heme Synthesis in what tissues and for what?
Everywhere heme is needed but mainly bone marrow; synthesized for RBC’s (bone marrow) and cytochrome (in liver)
Steps of Heme Synthesis (5 of them)
- Under low heme conditions, ALA synthase becomes active and converts succinyl-CoA + glycine —-> aminolevulinic acid (ALA); ALA synthase localized in mito since it can easily pick up succinyl-CoA there from CAC cycle
- ALA is exported to cytosol where 2xALA—-(PBG synthase/ALA dehydratase)—> Porphobilinogen (PBG)
- 4x PBG—–(Uroporphyrinogen (UPG) synthase III)—>UPG III, which is a photoactive molecule
- Modifications of UPG III side chains occur in cytsol AND mito generating first coporphyrinogen (CPG III) and second Protoporhyrinogen IX as intermediates
- In mito, Protoporphyrinogen IX —-(ferrochelatase)—> heme; (Fe2+ added to molecule)
Regulation of Heme Synthesis and Consequences of Alcohol Consumption
regulated at committed step ALA synthase by end product (heme inhibition); this end product inhibition explains increase in hepatic heme synthesis in response to alcohol and drugs; Alcohol induces MEOS (requires cytochrome p450 enzyme) which causes heme to be incorporated into cytop450 and increase in heme synthesis since the decrease in heme. Alcohol/drugs increase and worsen symptoms of those w/ heme synthesis disorders
Heme Synthesis Disorders (Alcohol Consumption)
if heme cannot be synthesized, there is no heme around to inhibit ALA synthase so heme pathway is constantly “ON”; the build up of intermediates of the pathway will be excreted or shunted to other pathways; these disorders called porphyrias; alcohol will trigger acute attack since it will induce heme pathway to become very active
Porphyria
Heme synthesis disorders; worsened by drugs/alcohol (due to MEOS)
Acute Intermittent Porphyria (AIP)
more common type; deficiency in Porphobilinogen Deaminase; ALA and PBG accumulate in circulation and urine giving urine dark red color; both compounds = neurological symptoms; life threatening, acute abdominal pain and confusion
Porphyria Cutanea Tarda (PCT)
deficiency of Uroporphyrinogen Decarboxylase (UROD); build up of porphyrins that can be detected in urine;in UV light urine from a PCT patient looks pink; porphyrins can absorb UV light so if this stuff accumulates light energy is discharged into tissues and generates reactive oxygen species; photosensitivity of skin
Lead Poisoning and Heme Synthesis
lead = inhibitor of porphobilinogen synthase and ferrochelatase; leads to accumulation of ALA and other heme precursors; symptoms similar to the porphyrias; lead in urine diagnosis
Degradation of Heme
Occurs in macrophages; heme released from RBC’s (ex.) and then Heme—->unconjugated bilirubin; will be bound by albumin and transported to liver; bilirubin will be conjugated in the liver by UGT
Bilirubin Conjugation and Clinical Significance of Direct vs. Indirect
once bilirubin is in liver (very hydrophobic) it will be made more hydrophilic by action of bilirubin -UDP glucuronyltransferase (UGT!!! remember deficiency in enzyme =’s Crijgler-Najjar or Gilbert Syndrome); 1 or 2 glucuronic acid molecules added to bilirubin to conjugate it; direct = conjugated and indirect = unconjugated –distinction is important for understanding etiology of jaundice
Bilirubin Excretion
Conjugated bilirubin is secreted by liver into biliary capillaries and through gall duct into gut; catabolized by bacteria to urobilinogens (removing glucuronic acid); spontaneous oxidation of urobilinogen gives urobilin (colored compound responsible for color of feces) and urobilin IS water soluble; small amount of urobilinogen is reabsorbed and transferred to liver/kidney and undergoes spontaneous conversion to urobilin which is excreted in urine (gives urine its color)
Pre-Hepatic Jaundice
caused by elevated destruction of RBC’s which can lead to serum conc. of bilirubin that exceed the capacity of the liver’s ability to handle them; leaves left over unconjugated bilirubin that is able to go into tissues and brain; characterized by elevated serum levels of indirect bilirubin;
Hepatic Jaundice
liver disease can impair its ability to conjugate bilirubin which leads to rise in indirect bilirubin in plasma and tissues; tissues damage and cirrhosis; pale color of feces and urine; caused by hepatitis or acetaminophen poisoning; watch for elevation of AST or ALT in serum too!
Post-Hepatic (Cholestatic) Jaundice
gallstones or neoplasias can obstruct bill duct which impair livers ability to excrete conjugated bilirubin into feces; so all conjugated bilirubin excreted by way of kidneys and urine; pale color of feces but intense color of urine; conjugated and unconjugated bilirubin in tissues; watch for other markers of blocked bile ducts like presence of alkaline phosphatase
