One ring to rule them all: trafficking of heme and heme synthesis intermediates in the metazoans

Abstract

The appearance of heme, an organic ring surrounding an iron atom, in evolution forever changed the efficiency with which organisms were able to generate energy, utilize gasses and catalyze numerous reactions. Because of this, heme has become a near ubiquitous compound among living organisms. In this review we have attempted to assess the current state of heme synthesis and trafficking with a goal of identifying crucial missing information, and propose hypotheses related to trafficking that may generate discussion and research. The possibilities of spatially organized supramolecular enzyme complexes and organelle structures that facilitate efficient heme synthesis and subsequent trafficking are discussed and evaluated. Recently identified players in heme transport and trafficking are reviewed and placed in an organismal context. Additionally, older, well established data are reexamined in light of more recent studies on cellular organization and data available from newer model organisms. This article is part of a Special Issue entitled: Cell Biology of Metals.

Figure 1

The mammalian heme biosynthetic pathway. The diagram presents the enzymatic steps and structures of intermediates in the pathway from ALA to heme. Steps that occur in the mitochondrion are enclosed in the dashed box and those outside the box are present in the cytosol. Regions highlighted in red show the site of chemical change catalyzed by the enzyme listed. Synthesis of ALA from glycine and succinyl CoA, which is the first committed step and occurs in the mitochondrion, is not shown. Abbreviations are as in the text.

Figure 2

Proposed model for components involved in heme synthesis. Details are discussed in the text and where specific data exist for a particular component, its name is shown. Components that are currently unidentified experimentally are denoted with “?”. Abbreviations and conventions are given in the text.

Figure 3

Cartoon of proposed interaction between protoporphyrinogen oxidase (PPOX) and FECH across the inner mitochondrial membrane. The initial PPOX-FECH docking model was published by Koch et al. [42] for plant PPOX and human FECH. The current model was derived from PDB files 3NKS (PPOX) and 2QD1 (FECH). FECH is colored green and PPOX is colored violet. Porphyrin atoms are depicted as red colored solid spheres and the PPOX inhibitor is shown in solid black. Phospholipids are presented as sticks that are colored wheat. Of note is that the crystal structures of FECH with bound porphyrin possess one protoporphyrin bound in the active site and a second one associated with the outer edge of the active site lip. This is proposed to be the entry route of porphyrin into the active site pocket [18, 90]. It is proposed that FECH and PPOX interact transiently across the membrane to facilitate transfer of protoporphyrin to FECH. Following this transfer FECH undergoes spatial alterations that are proposed to lower the affinity between FECH and PPOX so that their interaction ceases thereby allowing FECH to interact with MTF1 and later a heme accepting protein.

Figure 4

Model of FECH and mitoferrin in the inner mitochondrial membrane. Human FECH is shown as a cartoon colored green with bound protoporphyrin in red spheres. A structure of mitoferrin 1 is currently not available, but it will be highly homologous to the structure of another inner mitochondrial solute transporter, the ATP/ADP transporter, whose structure has been solved [246] and is shown as a cartoon in red. Both proteins are oriented in a phospholipid bilayer (wheat colored). No structure of ABCB10 is available and the structures of known ABC transporters are so diverse as to make estimates of a structure model of ABCB10 not possible. The model is shown to demonstrate that interactions between FECH and MTF1 are possible given the relative sizes and spatial orientations in the membrane.