Dihydrodipicolinate

The overall fold of MIPS is similar to that of diaminopimelic acid dehydrogenase from Corynebacterium glutamicum and dihydrodipicolinate reductase from E. coli. Though the reactions catalyzed by these enzymes are quite different, they all use either NAD+ or NADP+ bound to a structurally similar Rossmann fold domain, and all three contain a (3 sheet domain located underneath the Rossmann fold and directly beneath the nicotinamide moiety that defines part of the active site (Norman et al., 2002 Stein and Geiger, 2002). 

Fig. 3. CLM (common ligand mimic) with linker to SL (substrate ligand) is prepared by computationally matching the pharmacophore properties of the nicotinamide ring of NADH bound to dihydrodipicolinate reductase (DHPR) (11).

Cirilli, M., Zheng, R., Scapin, G., and Blanchard, J.S. (2003) The three-dimensional structures of the Mycobacterium tuberculosis dihydrodipicolinate reductase-NADH-2,6-PDC and -NADPH-2,6-PDC complexes. Structural and mutagenic analysis of relaxed nucleotide specificity. Biochemistry 42, 10644-10650. 

A further flux control step within L-lysine synthesis is the aspartate semialdehyde branch point. The aldehyde is either used as a substrate for the homoserine dehydrogenase, or together with pyruvate as a substrate for the dihydrodipicolinate synthase (Fig. 10). Whereas the homoserine dehydrogenase is allosterically controlled in its catalytic activity by the L-threonine concentration... 

Shiio, I. (1990) Threonine production by dihydrodipicolinate synthase-defective mutants of Brevibacterium flavum. Biotechnol Adv., 8 (1), 97-103. 

Fig. 1. Bio thetic pathways for the essential aspartate-family amino adds. The numbers represent enzymes catalyzing the reaction 1, aspartate kinase 2, homoserine dehydrogenase 3, homoserine kinase 4, threonine thase 5, threonine dehydrogenase 6, acetolactate thase 7, dihydrodipicolinate thase 8, diaminopimelate decarboiylase.

A number of other nonprotein amino acids are involved in the biosynthesis of lysine (Fig. 13.5). Among these are 2,3-dihydrodipicolinic acid (19), A -succinyl-2,6-diaminop-imelic acid (20), and 2,6-diaminopimelic acid (21). 

Dihydrodipicolinate synthase 2 dihydrodipicolinate dehydrogenase 3 spontaneous reaction 4 succinylase 5 succinyldiaminopimelate aminotransferase 6 succinyldiaminopimelate de-succinylase 7 diaminopimelate epimerase 8 diaminopimelate decarboxylase... 

Aspartate 4-semialdehyde, seen, for example, in Scheme 12.13, which provided a pathway for the biosynthesis of the essential amino acid methionine (Met, M) and in Scheme 12.14, which holds a representation of the biosynthesis of threonine (Thr, T), is also a place to begin to describe a pathway to lysine (Lys, K). As shown in Scheme 12.19, aspartate 4-semialdehyde undergoes an aldol-type reaction with pyruvate (CHsCOCO ") in the presence of dihydropicoUnate synthase (EC 4.2.1.52) to produce a series of intermediates that, it is presumed, lead to (5)-23-dihydropyridine-2,6-dicarboxylate. Then, dihydrodipicolinate reductase (EC 1.3.1.26) working with NADPH produces the tetrahydropyridine, (S)-2,3,4,5-tetrahydropyridine-2,6-dicarboxylate.This heterocycle, in the presence of glutamate (Glu, E) and water, is capable of transamination directly to 2-oxoglutarate and (2S, 6S)-2,3-diaminopimelate in the presence of LL-diaminopimelate aminotransferase (EC 2.6.1.83), while the latter, in the presence of the pyridoxal dependent racemase... 

Dihydrodipicolinate synthase dapA Consume L-aspartyl semialdehyde to produce L-lysine... 

Regulation of lysine biosynthesis. ASA, aspartate-p-semialdehyde DHDP, dihydrodipicolinate DAP, a, e-diaminopimelate and Hse, homoserine. (1) Aspartate kinase,... 

These characteristics of lysine production were combined to make strains that were much more efficient producers. In addition, the introduction of a leucine-requiring mutation also increases the amount of lysine, since in the mutant dihydrodipicolinate synthase is released from repression hy leucine. 

The genes of the enzymes responsible for the biosynthesis of lysine in Corynebacterium have been cloned, and their nucleotide sequences are known. These genes include aspartokinase, aspartate semialdehyde dehydrogenase, dihydrodipicolinate... 

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