This superfamily consists of the NADPH binding domain found in bacterial and archaeal enzymes with malate, L-lactate, L-sulpholactate dehydrogenase activities. The malate dehydrogenase (MDH) of some extremophilies is more similar to the L-lactate dehydrogenases (L-LDH) from various sources than to other MDHs. The archaebacterial MDH deviates from the eubacterial and eukaryotic enzymes having a low selectivity for the coenzyme (NAD(H) or NADP(H)) and catalysing the reduction of oxaloacetate to malate more efficiently than the reverse reaction. It has been suggested that this class of dinucleotide cofactor-dependent dehydrogenases do not contain a Rossman-fold motif, as it was prior believed to be the case. The domain is also found in a variety of enzymes, such as: bacterial and archaeal NAD(P)-dependent malate and lactate dehydrogenases including MjSLDH from thermophilic methanogen Methanocaldococcus jannaschii, (S)-ureidoglycolate dehydrogenase (AllD), and 2,3-diketo-L-gulonate reductase (YiaK) from E. coli.

The Methanoarchaeal sulpholactate dehydrogenase MjSLDH is a dimer, each polypeptide chain being organised in two domains - the largest domain, a dinucleotide-binding domain that contains both chain termini and most of the active site residues and a mobile domain that covers the active site. This co-enzyme binding domain is described to be a triangular wedge made up of a central, seven-stranded mixed beta-sheet, sandwiched between three helices on one side and two helices on the other side.

The Pseudomonas syringae homologous dimeric enzyme is PsDpkA, whose monomer is composed of 3 different domains - domain I, domain II (NADPH binding domain), and domain III. Domain I is the helical domain represented in this superfamily, and is described to have a pseudo four-helix bundle structure. The core of the NADPH binding domain consists of a seven-stranded predominantly antiparallel beta-sheet fold (also known as SESAS), which is specific to the MDH/LDH superfamily. Domains I and III are mobile and change their conformations as rigid bodies to produce the catalytic form upon substrate binding. The conformational change to the catalytic form plays important roles in substrate recognition and the catalytic process. The NADPH binding cavity is formed at the domain interface and at the subunit interface with the nicotinamide-ribose moiety of NADPH directly interacting with one side of the antiparallel beta-sheet of domain II. Domain II forms the NADPH binding site and has an open alpha/beta structure with four alpha helices and eleven beta-strands.

Another member of this superfamily is (S)-ureidoglycolate dehydrogenase (AllD), an enzyme involed in nitrogen metabolism which converts (S)-ureidoglycolate, a key intermediate in the purine degradation pathway, to oxalurate in an NAD(P)-dependent manner. It also folds into three distinct domains - domain I, domain II and domain III. Domain II contains N- and C-terminal regions and consists of the four-helix bundle similarly to the other enzymes previously described. In the dimer, Domain II from each subunit interacts extensively with each other, in a face-to-face orientation, between the central beta-sheet and two helices alpha7 and 8.

PFAM:PF02615, INTERPRO:IPR036111,PMID:15014443,PMID:16192274,PMID:23284870,PMID:14718529