Heme - Degradation

Degradation

Degradation begins inside macrophages of the spleen, which remove old and damaged erythrocytes from the circulation. In the first step, heme is converted to biliverdin by the enzyme heme oxygenase (HOXG). NADPH is used as the reducing agent, molecular oxygen enters the reaction, carbon monoxide (CO) is produced and the iron is released from the molecule as the ferric ion (Fe3+).

In addition, heme degradation appears to be an evolutionary conserved response to oxidative stress. Briefly, when cells are exposed to free radicals, there is a rapid induction of the expression of the stress responsive heme oxygenase-1 (Hmox1) isoenzyme that catabolizes heme (see below). The reason why cells must increase exponentially their capability to degrade heme in response to oxidative stress remains unclear but this appears to be part of a cytoprotective response that avoids the deleterious effects of free heme.

HMOX1/2 heme --------------> biliverdin + Fe3+ / \ H+ + NADPH NADP+ O₂ CO

In the second reaction, biliverdin is converted to bilirubin by biliverdin reductase (BVR):

BVR biliverdin -----------> bilirubin / \ H+ + NADPH NADP+

Bilirubin is transported into the liver bound to a protein (serum albumin), where it is conjugated with glucuronic acid to become more water soluble. The reaction is catalyzed by the enzyme UDP-glucuronide transferase (UDPGUTF).

UDPGUTF bilirubin + 2 UDP-glucuronate ------------> bilirubin diglucuronide \ 2 UMP + 2 Pi

This form of bilirubin is excreted from the liver in bile. The intestinal bacteria deconjugate bilirubin diglucuronide and convert bilirubin to urobilinogens. Some urobilinogen is absorbed by intestinal cells and transported into the kidneys and excreted with urine (urobilin, which is the product of oxidation of urobilinogen, is responsible for the yellow colour of urine). The remainder travels down the digestive tract and is converted to stercobilinogen. This is oxidized to stercobilin, which is excreted and is responsible for the color of feces.