Lactate dehydrogenase structure

Everse, J., Kaplan, N.O. Lactate dehydrogenase Structure and function. Advanc. Enzymol. 37, 61-133 (1973)... 

Figure 8.10 The quaternary structure of proteins. The enzyme lactate dehydrogenase (EC 1.1.1.27) has a relative molecular mass of approximately 140 000 and occurs as a tetramer produced by the association of two different globular proteins (A and B), a characteristic that results in five different hybrid forms of the active enzyme. The A and B peptides are enzymically inactive and are often indicated by M (muscle) and H (heart). The A4 tetramer predominates in skeletal muscle while the B4 form predominates in heart muscle but all tissues show most types in varying amounts.

The isoenzymes within a particular family will operate under slightly different circumstances or may respond differently to metabolite feedback regulation. In this case there is some degree of structural similarity between the different isoenzymes. The usual example used to illustrate this point is lactate dehydrogenase (LD), which has five isoenzymes, each composed of four sub-units. The subunits are of two types, H or M, so the five forms arise as follows ... 

Fig. 22. An example of a long two-stranded ribbon of antiparallel jS structure, from lactate dehydrogenase (residues 263-294). Side chains are not shown hydrogen bonds are dotted. As is typical of isolated two-stranded ribbons, the chains show a very strong twist (180° in about five residues).

The doubly wound structures were first recognized as a category by Rossmann in comparing flavodoxin with lactate dehydrogenase dl. As more and more protein structures were solved which fell into this... 

The darkest inner box in Fig. 93 includes those classic doubly wound parallel sheets that exactly match the topology of lactate dehydrogenase dl. Phosphorylase domain 2 is a five-layer structure in... 

The remaining three antiparallel /3 structures form a miscellaneous category (see Fig. 84). Lactate dehydrogenase d2 and gene 5 protein each has several two-stranded antiparallel j8 ribbons, but they do not coalesce into any readily described overall pattern. The N-terminal domain of tomato bushy stunt virus protein has a unique /3 structure in which equivalent pieces of chain from three different subunits wrap around a 3-fold axis to form what has been called a /3 annulus (Harrison et ah, 1978). Each of the three chains contributes a short strand segment to each of three three-stranded, interlocking /3 sheets. This domain provides one of the subunit contacts that hold the virus... 

Lactate dehydrogenase (LDH, EC 1AA.27) is discussed in some detail here and on the next page as an example of the structure and function of an enzyme. 

The active center of an LDH subunit is shown schematically in Fig. 2. The peptide backbone is shown as a light blue tube. Also shown are the substrate lactate (red), the coenzyme NAD (yellow), and three amino acid side chains (Arg-109, Arg-171, and His-195 green), which are directly involved in the catalysis. A peptide loop (pink) formed by amino acid residues 98-111 is also shown. In the absence of substrate and coenzyme, this partial structure is open and allows access to the substrate binding site (not shown). In the enzyme lactate NAD"" complex shown, the peptide loop closes the active center. The catalytic cycle of lactate dehydrogenase is discussed on the next page. 

Most dehydrogenases that use NAD or NADP bind the cofactor in a conserved protein domain called the Rossmann fold (named for Mchael Rossmann, who deduced the structure of lactate dehydrogenase and first described this structural motif). The Rossmann fold typically consists of a six-stranded parallel /3 sheet and four associated a helices (Fig. 13-16). 

RGURE 13-16 The nucleotide binding domain of the enzyme lactate dehydrogenase, (a) The Rossmann fold is a structural motif found in the NAD-binding site of many dehydrogenases It consists of a six-stranded parallel /3 sheet and four a helices inspection reveals the arrangement to be a pair of structurally similar motifs... 

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