Enzymes regulated via cystathionine β-synthase domains

Abstract

Cystathionine β-synthase (CBS) domains discovered 20 years ago can bind different adenosine derivatives (AMP, ADP, ATP, S-adenosylmethionine, NAD, diadenosine polyphosphates) and thus regulate the activities of numerous proteins. Mutations in CBS domains of enzymes and membrane transporters are associated with several hereditary diseases. The regulatory unit is a quartet of CBS domains that belong to one or two polypeptides and usually form a conserved disk-like structure. CBS domains function as "internal inhibitors" in enzymes, and their bound ligands either amplify or attenuate the inhibitory effect. Recent studies have opened a way to understanding the structural basis of enzyme regulation via CBS domains and widened the list of their bound ligands.

Enhanced functionalisation of major facilitator superfamily transporters via fusion of C-terminal protein domains is both extensive and varied in bacteria

“…The presence of two CBS domains is consistent with the usual arrangement found in CBS-containing proteins [35]. These domains are able to bind nucleotides, typically ATP, allowing regulation of enzymatic activity and/or oligomerisation state in relation to the internal concentration of ATP (and potentially also inhibitory nucleotides, such as GTP in eukaryotic IMPDH enzymes) [36]. Two homologous CBS-containing MFS transporters, Bifidobacterium breve BBr_0838 and Bifidobacterium longum BL0920, have been characterised.…”

Revisiting the methionine salvage pathway and its paralogues

“…With reference to metabolic engineering, we must add a final comment to the understanding of this stage of the MSP. As a consequence of its pervasive presence, MTA regulates, directly or indirectly, expression, activity or both, of enzymes involved in methionine, AdoMet or polyamine biosynthesis (Anashkin et al, 2017). Being similar to AdoMet, but smaller, MTA often interferes with AdoMet synthesis or other processes (see for example Pang et al, 2017), with a variety of consequences on methionine availability, including inhibition of virulence of pathogens and production of antibiotics (Tojo et al, 2014;Wang et al, 2017;Bourgeois et al, 2018).…”

Allosteric regulation accompanied by oligomeric state changes of Trypanosoma brucei GMP reductase through cystathionine-β-synthase domain

“…Opposite modulation of TbGMPR activity by purine nucleotides. Enzymes harboring a CBS domain usually change their activities in the presence of purine nucleotides [10][11][12] ; therefore, we sought to examine whether purine nucleotides modify the activity of TbGMPR. In the presence of GTP, the initial velocity of TbGMPR was upregulated in a concentration-dependent manner (Fig.…”