Abstract
Iron-sulfur (Fe-S) clusters are essential protein cofactors. In enzymes, they are present either in the rhombic [2Fe-2S] or the cubic [4Fe-4S] form, where they are involved in catalysis and electron transfer and in the biosynthesis of metal-containing prosthetic groups like the molybdenum cofactor (Moco). Here, we give an overview of the assembly of Fe-S clusters in bacteria and humans and present their connection to the Moco biosynthesis pathway. In all organisms, Fe-S cluster assembly starts with the abstraction of sulfur from l-cysteine and its transfer to a scaffold protein. After formation, Fe-S clusters are transferred to carrier proteins that insert them into recipient apo-proteins. In eukaryotes like humans and plants, Fe-S cluster assembly takes place both in mitochondria and in the cytosol. Both Moco biosynthesis and Fe-S cluster assembly are highly conserved among all kingdoms of life. Moco is a tricyclic pterin compound with molybdenum coordinated through its unique dithiolene group. Moco biosynthesis begins in the mitochondria in a Fe-S cluster dependent step involving radical/S-adenosylmethionine (SAM) chemistry. An intermediate is transferred to the cytosol where the dithiolene group is formed, to which molybdenum is finally added. Further connections between Fe-S cluster assembly and Moco biosynthesis are discussed in detail.
Highlights
As one of the most abundant metals on earth, iron naturally is one of the prevalent metal ions in biological systems [1]
The first step of molybdenum cofactor (Moco) biosynthesis, the conversion of GTP into cyclic pyranopterin monophosphate (cPMP), directly depends on the assembly of [4Fe-4S] clusters, which proceeds through a complex rearrangement reaction, where C8 of guanine is being inserted between C20 and C30 of ribose [60]
The first step of Moco biosynthesis, the conversion of GTP into cPMP, directly depends on the assembly of [4Fe-4S] clusters, which proceeds through a complex rearrangement reaction, where C8 of guanine is being inserted between C2′ and C3′ of ribose [60]
Summary
As one of the most abundant metals on earth, iron naturally is one of the prevalent metal ions in biological systems [1]. 1990s, the proteins involved in Fe-S cluster biosynthesis have been studied and characterized While these studies provided a general outline of in vitro and in vivo Fe-S cluster assembly, a number extensively. These three systems and nuclear Fe-S proteins depends on the mitochondrial ISC assembly machinery These three are highly conserved in eukaryotes from humans to yeast and plants. SufS forms a complex with SufE, which together mobilize the sulfur for cluster assembly. While the ISC system is the house-keeping Fe-S cluster assembly system, the SUF system instead is mainly synthesized under iron-limiting conditions [24]. In its apo-form, IscR activates the expression of the SUF system (Figure 3) [4] This mechanism allows IscR to fine-tune Fe-S cluster synthesis in response to the presence of synthesized Fe-S clusters and iron availability in the cell.
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