Control of intracellular heme levels: Heme transporters and heme oxygenases

Abstract

Heme serves as a co-factor in proteins involved in fundamental biological processes including oxidative metabolism, oxygen storage and transport, signal transduction and drug metabolism. In addition, heme is important for systemic iron homeostasis in mammals. Heme has important regulatory roles in cell biology, yet excessive levels of intracellular heme are toxic; thus, mechanisms have evolved to control the acquisition, synthesis, catabolism and expulsion of cellular heme. Recently, a number of transporters of heme and heme synthesis intermediates have been described. Here we review aspects of heme metabolism and discuss our current understanding of heme transporters, with emphasis on the function of the cell-surface heme exporter, FLVCR. Knockdown of Flvcr in mice leads to both defective erythropoiesis and disturbed systemic iron homeostasis, underscoring the critical role of heme transporters in mammalian physiology.

Kidney Cadmium Toxicity, Diabetes and High Blood Pressure: The Perfect Storm

“…In an adult human, a total of 400 mg bilirubin is produced per day (Khan and Quigley 2011). HO-1 and HO-2 both contribute to basal serum bilirubin levels.…”

Emerging Roles of Cadmium and Heme Oxygenase in Type-2 Diabetes and Cancer Susceptibility

“…There are further differences between these two proteins to suggest that each may participate in cell functions other than iron recycling. HO-1 and HO-2 both are localised to the endoplasmic reticulum, while HO-1 has also been localized to mitochondria, nucleus and plasma membrane caveolae together with nitric oxide synthase and biliverdin reductase (Khan and Quigley 2011). The presence of HO-1 in the nucleus suggests that HO-1 may also have a regulatory role on gene expression.…”

“…This makes heme degradation by HO-1 and HO-2 indispensable. Two other products of heme degradation, namely carbon monoxide (CO) and bilirubin, are known for their anti-inflammatory and antioxidant properties (Shibahara 2003;Shibahara et al 2007;Khan and Quigley 2011). These add to the biological importance of the HO-1 and HO-2 enzyme system.…”

“…Iron recycling: In concert with NADPH-cytochrome P450 reductase, HO-1 and HO-2 catalyse heme degradation with the resultant release of iron, carbon monoxide (CO) and biliverdin IXα (Shibahara 2003;Shibahara et al 2007;Khan and Quigley 2011). Biliverdin IXα is converted to bilirubin almost instantly by biliverdin reductase.…”

“…Degradation of heme by HO-1 and HO-2 to retrieve iron occurs at the expense of the reducing equivalent NADPH (H+). In an adult human, about 75% of the total 400 mg bilirubin produced daily is derived from hemoglobin (Khan and Quigley 2011). The economy of iron utilization requires salvaging of iron so the bulk of iron release by HO-1 and HO-2 is reutilized in the synthesis of hemoglobin and other hemoproteins, including nitric oxide synthase, various enzymes of the mitochondrial respiratory chain and Table 2.…”