Biosynthesis of heme in mammals

Abstract

Most iron in mammalian systems is routed to mitochondria to serve as a substrate for ferrochelatase. Ferrochelatase inserts iron into protoporphyrin IX to form heme which is incorporated into hemoglobin and cytochromes, the dominant hemoproteins in mammals. Tissue-specific regulatory features characterize the heme biosynthetic pathway. In erythroid cells, regulation is mediated by erythroid-specific transcription factors and the availability of iron as Fe/S clusters. In non-erythroid cells the pathway is regulated by heme-mediated feedback inhibition. All of the enzymes in the heme biosynthetic pathway have been crystallized and the crystal structures have permitted detailed analyses of enzyme mechanisms. All of the genes encoding the heme biosynthetic enzymes have been cloned and mutations of these genes are responsible for a group of human disorders designated the porphyrias and for X-linked sideroblastic anemia. The biochemistry, structural biology and the mechanisms of tissue-specific regulation are presented in this review along with the key features of the porphyric disorders.

Butyric acid retention in gingival tissue induces oxidative stress in jugular blood mitochondria

“…The mitochondria is the site of heme biosynthesis (Ponka 1997) and its product, heme, serves as a prosthetic group in many essential enzymes involved in electron transport, detoxification, antioxidant activity, nitrogen monoxide synthesis, oxygen transport, and apoptosis (Ajioka et al 2006). In addition, the mitochondria play an important role in redox signaling (Daiber 2010) and utilize several mechanisms to amplify ROS formation needed for ROS-dependent signaling (Brandes 2005;MacMillan-Crow et al 1998;Radi et al 2002).…”

A Pentapeptide Motif Related to a Pigment Binding Site in the Major Light-Harvesting Protein of Photosystem II, LHCII, Governs Substrate-Dependent Plastid Import of NADPH:Protochlorophyllide Oxidoreductase A

“…Deregulation of mitochondrial porphyrin metabolism in fact causes disease and cell death (e.g. May et al, 1990;Ajioka et al, 2006). Last but not least, the import of the major light-harvesting protein of PSII, LHCII, into chloroplasts has been demonstrated to be dependent on chlorophyll(ide) b in vitro (Reinbothe et al, 2006).…”

Effect of an oral iron chelator or iron-deficient diets on uroporphyria in a murine model of porphyria cutanea tarda

“…This suggests that L1 preferentially depletes iron from a different pool of hepatic iron, that is, the postulated free iron pool that is involved in the oxidative process that is thought to result in inactivation of uroporphyrinogen decarboxylase and hence the subsequent development of uroporphyria. 1,2 The question arises as to whether the action of L1 on URO accumulation is mainly due to the depletion of the hepatic active iron pool through excretion of the iron-L1 chelate. L1 may also prevent URO accumulation by the formation of an Fe-L1 chelate that is not redox-active.…”

“…Most cases are sporadic rather than familial. 1,2 There are several associated risk factors, including the consumption of alcoholic beverages and increased body iron stores. [1][2][3] PCT patients usually display hepatic siderosis, and the disease is responsive either to phlebotomy, which presumably acts through iron depletion, or a treatment with low-dose chloroquine or hydroxychloroquine.…”

“…[1][2][3] PCT patients usually display hepatic siderosis, and the disease is responsive either to phlebotomy, which presumably acts through iron depletion, or a treatment with low-dose chloroquine or hydroxychloroquine. 1,2 In addition, some PCT patients have quite high levels of hepatic iron associated with the common mutations in the HFE gene (C282Y and H63D), 4,5 which are also found in hereditary hemochromatosis (type I).…”