Heme degradation and human disease: diversity is the soul of life.
We all depend on molecular oxygen and heme for our life, as evident from the pigments in blood and daily wastes. About 80% of serum bilirubin is derived from hemoglobin of senescent erythrocytes, which have finished their mission of 120 days and have been phagocytized by macrophages in the reticuloendothelial system. Here we present an overview of the heme degradation processes and relevant disorders by focusing on heme oxygenase-1 (HO-1), a key enzyme in heme catabolism. HO-1 cleaves the porphyrin macrocycle of heme at the expense of molecular oxygen to release a linear tetrapyrrole biliverdin, carbon monoxide, and ferrous iron; biliverdin is rapidly reduced to bilirubin. Bilirubin is transported to the liver (hepatocytes), conjugated with glucuronic acid by bilirubin UDP-glucuronosyltransferase, and excreted into bile. Genetic diversity, a strategy in the host defense, is seen in the human ho-1 and UDP-glucuronosyltransferase genes. Moreover, striking interspecies variations are noted in the regulation of HO-1 expression by hypoxia, heat shock, or interferon-gamma, each of which mainly represses HO-1 expression in human cells. Implications of such a variety are discussed in relevance to the pathogenesis of severe malaria caused by Plasmodium falciparum, the most ancient foe of humans.
Shibahara
Shigeki
S
Department of Molecular Biology and Applied Physiology, Tohoku University School of Medicine, Aoba-ku, Sendai, Miyagi 980-8575, Japan. shibahar@mail.cc.tohoku.ac.jp
Kitamuro
Tomomi
T
Takahashi
Kazuhiro
K
D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000378:metabolism; D001663:Bilirubin / Q000737:chemistry / Q000378:metabolism*; D002248:Carbon Monoxide / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000201:enzymology; D003414:Crigler-Najjar Syndrome / Q000201:enzymology; D015971:Gene Expression Regulation, Enzymologic; D005878:Gilbert Disease / Q000201:enzymology; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism*; D006418:Heme / Q000378:metabolism*; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism*; D051547:Heme Oxygenase-1; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007567:Jaundice, Neonatal / Q000201:enzymology; D008288:Malaria / Q000201:enzymology; D008565:Membrane Proteins; D009422:Nervous System Diseases / Q000201:enzymology; D010100:Oxygen / Q000378:metabolism
D000975:Antioxidants; D007527:Isoenzymes; D008565:Membrane Proteins; D006418:Heme; D002248:Carbon Monoxide; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D014453:Glucuronosyltransferase; D001663:Bilirubin; D010100:Oxygen