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• _4 value "Nearly four decades ago, an NADH-dependent enzyme that converts biliverdin to bilirubin was described (55). Later this enzyme was defined as an NADPH-dependent reductase (58). A decade later, the enzyme, known as \"biliverdin reductase\" (BVR) was obtained in homogeneous form and its unique dual pH/cofactor activity profile was revealed (27). The reductase activity is NADH dependent at acidic pH, whereas NADPH is used in the basic range. Searching for the molecular basis for this feature of BVR has recently culminated in unraveling other fascinating secrets of a protein with an uncanny spectrum of potential functions in cellsignaling pathways. Those functions, together with its unique structural features, underscore the central role of this unusual protein in cell signaling. BVR: Structure, Regulation, and Reductase Activity BVR is not exclusive to mammals, contrary to the general perception. The protein is evolutionarily conserved, and not only is it present across metazoa, but a homolog of mammalian reductase is also found in red algae (3, 53). Comparison of mammalian BVR protein sequences with those of chicken, Xenopus, and puffer fish reveals a high degree of conservation (FIGURE 1). The average sequence identity between mammalian species is >80%, with conservation of certain key features (13, 24, 36) denoted in FIGURE 1. Among those are the leucine zipper (bzip) motif (LX6LX6L/KX6LX6L), adenine dinucleotide- binding motif (GXGXXG), serine/threonine kinase domain [G(T/S)XX(F/Y)XAPE], Src homology (SH2)-binding domains (YMXM and YSLF), and Zn/metal-binding motif (H/CX10C-C/H). These features, as discussed below, are likely to have key function(s) in cell-signaling activities of BVR. There is apparently sequence polymorphism in human (h)BVR in the NH2-terminal amino acid of the mature protein. The primary sequences report- ed for the human gene by Japanese and US groups differ at position 3, having either threonine or alanine (24, 36). In most species, with the exception of the mouse, alanine is the encoded residue (FIGURE 1). The first two residues of BVR are deleted during the maturation process (13). The addition of an extra phosphoacceptor residue, threonine, could potentially affect structure, function, or stability of the protein. BVR reduces C10 (gamma-bridge) of biliverdin IXalpha, a product of heme (Fe-protoporphyrin IX) degradation by heme oxygenase (HO) isozymes HO-1 and HO-2, which catalyze the isomer-specific cleavage of heme at the alpha-methene carbon bridge. Plants use biliverdin IXalpha, produced by ferredoxindependent HO (3), to synthesize phytochromes, the sensory photoreceptors, to modulate their growth. The reaction, as characterized for Arabidopsis, depends on a ferredoxin-dependent BVR (23). Although the structural basis for the unique dual pH/cofactor-dependence activity profile of BVR remains unsolved, substituting serine residues with alanine and solving the secondary structure of the rat BVR-NADH complex have offered some clues and have identified key residues in reductase activity. The primary structure of the rat BVR (13) and crystal structure of the rat BVR-enzyme-cofactor complex (22, 60) have implicated the NH2-terminal domain (Rossman fold) in dinucleotide binding. There is an extensive interaction between the two domains of BVR, the NH2-terminal (the cofactor-binding domain) and the COOH-terminal beta-sheet of BVR (22, 60) (FIGURE 2). Point mutation of residues that in BVR interact with the adenine nucleotide, including G17 (in the Walker homology domain), S149 [in the serine/threonine kinase domain (21)], and K92-H93 dipeptide [in \"oxidoreductase\" domain AGKHVLVEY (30)], all inactivate the reductase. Among these, S149 has proven to be essential for activity (30, 41, 51). Additionally, changing C73 in the rat BVR (C74 in hBVR) to alanine inactivates the enzyme, as it is involved in substrate/ cofactor binding (40). These mutations have nearl..." provenance.