Diversity of Globin Function: Enzymatic, Transport, Storage, and Sensing*

The availability of genomic information from the three kingdoms of life has altered substantially our view of the globin superfamily. It is now evident that Hbs,2 defined as hemeproteins comprising five to eight -helices (A–H), with an invariant His at position F8 providing the proximal ligand to the heme iron, occur as three families in two structural classes (1). Within each family, the Hb can be either chimeric or SD. Historically, the first members of the two families that display the canonical 3/3 -helical fold were chimeric: the FHbs in Escherichia coli and yeast discovered in 1990, consisting of an N-terminal Hb coupled to a ferredoxin reductase-like domain, and the GCSs reported in bacteria and Archaea a decade later, comprising anN-terminalHb linked to variable gene regulatory domains. The third family of Hbs discovered concomitantly in algae, ciliates, and bacteria were the 2/2Hbs (“truncated” Hbs), which exhibit a 2/2 -helical fold (see supplemental figure). More recently, SD globins have been discovered in the FHb-like and sensorHb families that we have called SDFgbs and SDSgbs, respectively (2, 3). Fig. 1 shows diagrammatically the three Hb families and summarizes their distribution in bacteria and eukaryotes. A classification of Hbs is presented in the supplemental table. Only bacteria have representatives of all three families in chimeric and SD guise; the Archaea and eukaryotes lack FHbs and GCSs, respectively. On the basis of the higher sequence similarity to bacterial FHbs/SDFgbs than toGCSs and 2/2Hbs and the presence of FHbs/SDFgbs in unicellular eukaryotes, we have proposed that all eukaryoticHbs, including vertebrate / -globins,Mbs, Ngbs, andCygbs and all the invertebrate and plant Hbs, emerged from one or more ancestral bacterial SDFgbs (2). The variety of Hbs in bacteria makes it clear that the familiar O2 transport function of vertebrate Hbs is a relatively recent adaptation and that the early Hb functions must have been enzymatic andO2-sensing. In this review,wewill not discussO2 transport by animal (metazoan) Hbs; instead, we will focus on the reactions and functions of the FHbs/SDFgbs in the first five sections. The functions of the remaining two globin families will be discussed in the last two sections.