Conserved pairs of CBS sequence motifs (named after cystathionine β-synthase) found in a wide variety of proteins associate to form Bateman domains. A new study establishes that Bateman domains bind adenosyl compounds and regulate IMP dehydrogenase, CBS, chloride channels, and AMP-activated protein kinase. This discovery reveals how mutations in CBS sequences in these proteins cause hereditary diseases and provides a rich vista of conceptual opportunities for therapies in energy metabolism, obesity, diabetes, cancer, antivirals, and immunosuppression.

Alexander Bateman first recognized cystathionine β-synthase (CBS) sequences by looking for internal sequence duplications within proteins of the Methanococcus janaschii genome. These CBS sequences, typically 60 residues in length, occur as tandem pairs in a diversity of proteins, from archaebacteria to eukaryotes (1, 2), including IMP dehydrogenase (IMPDH), whose protein crystal structure shows that CBS sequence pairs form a discrete structural domain (3) termed a Bateman domain (Figure ​(Figure1)1) (4). Although it is known that mutations in CBS sequences alter the control functions of their parent proteins and cause hereditary diseases (5–7), the precise mechanisms involved were unknown. Mutations in CBS cause homocystinuria; IMPDH mutations cause retinitis pigmentosa; mutations in chloride channels (CLC1, CLC2, CLC5, and CLCKB) cause a variety of conditions, including congenital myotonia, idiopathic generalized epilepsy, hypercalciuric nephrolithiasis, and classic Bartter syndrome; mutations in the AMP-activated protein kinase (AMPK) γ2 subunit cause cardiac conductance problems similar to Wolff-Parkinson-White syndrome; and mutations in Hampshire pig γ3 cause skeletal muscle glycogen storage disease.

In this issue of the JCI, Scott and colleagues (8) have now found the missing link by showing that pairs of CBS sequences derived from AMPK, IMPDH-2, the chloride channel CLC2, and CBS bind adenosyl compounds (Figure ​(Figure1).1). They show that AMPK, with its two pairs of CBS sequences, binds two molecules of AMP or ATP; the single pair of CBS sequences present in IMPDH allows it to bind a single mole of ATP, as does the pair of CBS sequences in CLC2. CBS binds a single mole of S-adenosyl methionine. The authors introduced known hereditary mutations into CBS sequences of the parent protein and found that they caused dramatic shifts in ligand-binding properties, which explained the loss of allosteric control of the parent protein. These findings will also influence research into the wider family of CBS-containing proteins (2) that includes other ion transporters, hemolysin, and poly(A) polymerase.

IMPDH catalyzes the first committed step in the purine nucleoside-synthesis pathway for the generation of GMP. It converts IMP at the active site to xanthosine monophosphate, which is subsequently converted to GMP by GMP synthase. IMPDH activity is increased in proliferating cell types including cancers and activated peripheral blood lymphocytes. Because of this, IMPDH has been an important target for the design of anticancer and immunosuppressive drugs aimed at preventing cancer cell or lymphocyte proliferation. Drugs that inhibit IMPDH (e.g., ribavirin, myco-phenolic acid, and VX-497) reduce cellular GTP and deoxy-GTP levels and can also have broad antiviral activities against both RNA viruses, such as respiratory syncytial virus, and DNA viruses, such as hepatitis B virus and human cytomegalovirus (9). Scott et al. (8) show that IMPDH is activated by ATP binding to its pair of CBS sequences (evidenced by a fourfold increase in V_max) and propose that this dependence on ATP acts as a checkpoint to ensure that guanine nucleotide synthesis only proceeds when sufficient ATP is available. Much of the IMPDH inhibitor design has focused on the NAD⁺ cofactor– and IMP substrate–binding pockets within the active site. The findings of Scott et al. (8) now provide additional options for the design of IMPDH inhibitors that target the ATP-binding (allosteric activator) site; these options may offer improved specificity for immunosuppressive, anticancer, and antiviral chemotherapy. IMP also serves as a precursor for AMP synthesis via adenylsuccinate. In this pathway, AMP inhibits conversion of IMP to adenylsuccinate. This begs the question of whether adenylsuccinate could also bind the IMPDH ATP-binding site and activate IMPDH. If so, this would provide a further tier of control between the GMP and AMP synthetic pathways.