NAD(P)+ Binding to Dehydrogenases

Abstract

Each NAD‐dependent dehydrogenase binds its coenzyme in a unique manner. Virtually all possess a highly conserved binding domain called the Rossmann fold that is involved in this interaction and dictates the specificity of hydride transfer.

Keywords: NAD+; NADP+; dehydrogenases; rossmann fold; coenzyme; redox reactions

Figure 1.

(a) General representation of the coenzymes NAD+ and NADP+. The only difference between the two coenzymes is the presence or absence of a phosphate group on the 2‐hydroxyl of the ribose moiety adjacent to the adenine ring. (b) General scheme for NAD(P)+ and substrate, SH2, binding to a dehydrogenase. Illustrated is an order binding where the coenzyme binds first. Some dehydrogenases function with random binding. That is, either coenzyme or substrate can bind to the free enzyme. Depending upon rate constants, one may not detect all the intermediates shown in the figure.

Figure 2.

Oxidation and reduction of the nicotinamide ring by hydride ion. (a) The oxidized and reduced forms of the nicotinamide ring (in NAD(H)) of the coenzyme. The substrate‐binding site for some enzymes is on one side of the ring while for other enzymes it is on the other side. HA and HB indicate the hydride that would be transferred to the nicotinamide ring depending upon the side to which the substrate bound. (b) A structural representation of the alteration in the nicotinamide ring structure of NAD+ or NADP+ (green atoms) upon reduction to NADH or NADPH (orange atoms). The ribose ring is being held in the same position so that the movement of the nicotinamide can be seen. In the NAD+/NADP+ structure noncarbon atoms are coloured red for oxygen atoms and blue for nitrogen atoms.

Figure 3.

The hydrogen‐bonding interactions between the enzyme and the bound coenzyme in alcohol dehydrogenase (a) and aldehyde dehydrogenase (b). Some interactions are water‐mediated and are indicated with H2O. The structure of aldehyde dehydrogenase was solved in the presence of Mg2+ ions.

Figure 4.

Structural representation of a Rossmann domain from alcohol dehydrogenase. This structural motif is common among most of the NAD(P)+ dehydrogenases.

Figure 5.

Structural representation of part of the Rossmann domain showing the location of the conserved G‐X‐G‐X‐X‐G sequence and the conserved acidic residue (D/E) within the folded protein. The solid lines between the D/E residue and the coenzyme represent the hydrogen‐bonded interactions that help to select for NAD(H) rather than NADP(H) in alcohol dehydrogenase.

Figure 6.

Structural representation of pig aldose reductase (PDB ID code 1AH4) with bound coenzyme (NADP)+ shown in blue. Note the structural dissimilarity between aldose reductase and alcohol dehydrogenase (Figure ) in the area that binds the coenzyme.

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References

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Further Reading

Branden C and Tooze J (1991) Introduction to Protein Structure. New York: Garland Publishing.

Cornish‐Bowden A (1995) Fundamentals of Enzyme Kinetics. London: Portland Press.

Walsh C (1979) Enzyme Reaction Mechanisms. New York: WH Freeman and Co.

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How to Cite close
Weiner, Henry, and Hurley, Thomas D(May 2005) NAD(P)+ Binding to Dehydrogenases. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1038/npg.els.0003049]