The human iron-proteome†

Abstract

Organisms from all kingdoms of life use iron-proteins in a multitude of functional processes. We applied a bioinformatics approach to investigate the human portfolio of iron-proteins. We separated ironproteins based on the chemical nature of their metal-containing cofactors: individual iron ions, heme cofactors and iron-sulfur clusters. We found that about 2% of human genes encode an iron-protein.Of these, 35% are proteins binding individual iron ions, 48% are heme-binding proteins and 17% are iron-sulfur proteins. More than half of the human iron-proteins have a catalytic function. Indeed, we predict that 6.5% of all human enzymes are iron-dependent. This percentage is quite different for the various enzyme classes. Human oxidoreductases feature the largest fraction of iron-dependent family members (about 37%). The distribution of iron proteins in the various cellular compartments is uneven.In particular, the mitochondrion and the endoplasmic reticulum are enriched in iron-proteins with respect to the average content of the cell. Finally, we observed that genes encoding iron-proteins are more frequently associated to pathologies than the all other human genes on average. The present research provides an extensive overview of iron usage by the human proteome, and highlights several specific features of the physiological role of iron ions in human cells. Significance to metallomicsIron is one of the most ancient and abundant metal ions in living organisms: it participates in fundamental biological processes, such as photosynthesis, and respiration. It is an essential metal ion for humans. Here, we applied a bioinformatics approach to predict the entire set of human proteins that use iron as cofactor. We found that about 2% of human genes encode an iron-protein. In particular, 35% are proteins binding individual iron ions, 48% are heme-binding proteins and 17% are iron-sulfur proteins. Most of these proteins are enzymes: 37% of the human oxidoreductases need an iron ion to perform their catalytic mechanisms. The analysis of the subcellular location highlighted that some organelles are enriched in iron-proteins, in particular about 7% of the proteins localized in the endoplasmic reticulum and in the mitochondrion bind iron. Finally, our data show that mutations in genes encoding iron-binding proteins are more likely to be associated with pathology than all human genes on average.

Bioinformatics of Metalloproteins and Metalloproteomes

“…It combines the concepts of metal-binding domains (sequence profiles) and metal-binding patterns (residues coordinating the metal ion in 3D structures of metalloproteins), and examined their occurrence and correlation in all proteins of organisms. This strategy has been widely used for identification of metalloprotein genes and metalloproteomes for several essential metals (such as Zn, Cu, and Fe) in a variety of organisms from the three domains of life, which provides important clues to protein function and protein-ion interaction [25][26][27][28][29][30][31]. Based on this approach, a software package called RDGB was developed to identify putative homologs of the proteins of interest (such as metalloproteins) in any genome [32].…”

“…Zn and Fe are the two most commonly used trace metals in all organisms. A great number of proteins have been characterized or predicted to use one of the two metals (see references [25,26,30] and several web resources described above for a compiled list of Zn-or Fe-binding protein families). However, because of the widespread and complex use of the two metals, comparative analyses of the occurrence and evolutionary trends of their utilization are still very challenging to handle [69].…”

“…Another computational study compared the distribution of Fe-S proteins in more than 400 prokaryotic organisms with different life styles and found a strong relationship between environmental dioxygen levels and the usage of different Fe-S clusters [31]. Very recently, the complete human Fe proteome was systematically analyzed based on different types of Fe-containing cofactors [30]. About 2% of human genes encode Fe proteins (35%, 48%, and 17% for individual Fe ions, heme, and Fe-S clusters, respectively).…”

This preprint has been taken down.

“…The Glu-coordination is rare for heme-binding proteins, since His, Cys, Met, Try, and Lys are usually used as heme axial ligands 21,22,23,24,25,26 . The only instances have been reported for cytochrome bd from Geobacillus thermodenitrificans 27 and Escherichia coli 28,29 , in which heme b595 is ligated by Glu101 and Glu445, respectively.…”

A comprehensive mechanistic model of iron metabolism inSaccharomyces cerevisiae

“…3 Using bioinformatics methods, the ironome in human cells was found to involve 398 genes; 48% encode heme proteins, 35% encode mononuclear Fe and Fe-O-Fe proteins, and 17% encode iron-sulfur clusters (ISCs). 4 Such models are related to those I seek, but my objective goes beyond a statistical analysis; it is to obtain mechanistic insight at the systems' level analogous to that gained by viewing a busy metropolis from an altitude of 30 000 ft.…”