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Reductive stress

Nicotinamide adenine dinucleotide (NAD) is a ubiquitous biological redox cofactor. The oxidized form of NAD carries a positive charge and is denoted NAD+ while the reduced form is NADH (Figure 1). Reductive stress is induced by conditions which promote the formation of excessive intracellular NADH. Changes in NAD+/NADH ratio affect a plethora of cellular processes and is associated with several human diseases (for example age associated diseases and diabetes).

A representation of NAD

A representation of NAD showing the change that occurs in the nicotinamide moiety (encircled) when NAD+ is reduced to NADH. In NAD+, the nicotinamide moiety has a planar structure, whereas it is puckered in NADH as shown in this animation (avi).

In facultative aerobic bacteria the catabolism of fuel molecules is associated with the reduction of NAD+ to NADH. During the transition to oxygen limited growth, an increased level of NADH builds up, as it is less efficiently reoxidized to NAD+ as a result of reduced aerobic respiration. These roles of NADH and NAD+ provide a link between energy homeostasis and gene regulation. In most Gram-positive bacteria a novel sensor of the NAD redox balance is present. This transcriptional repressor is called Rex (from redox; Figure 2). Transcription of Rex-repressed genes in Bacillus subtilis is activated when oxygen is limiting for aerobic respiration, and as a consequence the levels of free NADH increase. This leads to production of cytochrome bd (a high-oxygen-affinity terminal oxidase), which ensures efficient oxygen usage, and LDH (lactate dehydrogenase), which recycles the excess of NADH. This part of our research is aimed at explaining how bacterial cells sense and respond to energy stress. It focuses on extensive functional and structural studies of Rex from various bacteria.

Rex

Rex is heterodimeric and consists of the two monomers: A and B (color coded green and blue, respectively), each which is subsequently divided into an N-terminal (lower part of the structures) and a C-terminal domain (upper part of the structures). The N-domains are splayed out in the open form (left) in comparison to the closed form (right). The longest diagonal through the Rex structure differs from 60 to 90 Å between the closed (NADH bound) and open (apo) form, respectively. The dynamic features of Rex have been outlined based on the crystal structures of one open form of the free, apo structure from Bacillus subtilis (PDB codes 2VT3and 2VT2 and another closed NADH-form from Thermus thermophilus HB8 (PDB code 2DT5).

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