Vitamin B6-dependent enzymes

The vitamin B6-dependent enzyme CBS catalyzes the first step, in which homocysteine reacts with serine to form L-cystathionine. In the second step, L-cystathionine is converted to L-cysteine, a-ketobutyrate, and ammonia by the vitamin B6-dependent enzyme cystathionase (7). 

Continuing the folate cycle, THF reacts with serine to produce 5,10-methylenetetrahydrofolate, a reaction catalyzed by the vitamin B6-dependent enzyme serine/glycine hydrox-ymethyltransferase. 

An important feature of the enzymatic systems is the presence of a binding site. Thus it is attractive to learn how to construct vitamin B6-dependent enzyme models that can provide a substrate binding site and perform molecular recognition. The first example was a catalyst (23) in which pyridoxamine was linked to the primary face of [1-cyclo-dextrin (P-CD) through a sulfur atom [15]. Catalyst 23 could transform a-keto acids into a-amino acids, as pyridoxamine does, but with selectivity. That is, phenylpyruvic acid... 

The transsulfuration pathway involves conversion of homocysteine to cysteine by the sequential action of two pyridoxal phosphate (vitamin B6)-dependent enzymes, cystathionine- 5-synthase (CBS) and cystathionine y-lyase (Fig. 21-2). Transsulfuration of homocysteine occurs predominantly in the liver, kidney, and gastrointestinal tract. Deficiency of CBS, first described by Carson and Neill in 1962, is inherited in an autosomal recessive pattern. It causes homocystinuria accompanied by severe elevations in blood homocysteine (>100 (iM) and methionine (>60 (iM). Homocystinuria due to deficiency of CBS occurs at a frequency of about 1 in 300,000 worldwide but is more common in some populations such as Ireland, where the frequency is 1 in 65,000. Clinical features include blood clots, heart disease, skeletal deformities, mental retardation, abnormalities of the ocular lens, and fatty infiltration of the fiver. Several different genetic defects in the CBS gene have been found to account for loss of CBS activity. 

Hennig M, Griimn B, Contestabile R, John RA, Jansonius JN. Crystal structure of glutamate-1-semialdehyde aminomutase an alpha 2-dimeric vitamin B6-dependent enzyme with asymmetry in structure and active site reactivity. 1997 94 4866-4871. 

G. Schneider, H. Kack, and Y. Lindqvist. 2000. The manifold of vitamin B6 dependent enzymes Structure FoldDes. 8 R1-R6. (PubMed)... 

Homocysteine is metabolized in the liver, kidney, small intestine and pancreas also by the transsulfuration pathway [1,3,89]. It is condensed with serine to form cystathione in an irreversible reaction catalyzed by a vitamin B6-dependent enzyme, cystathionine-synthase. Cystathione is hydrolyzed to cysteine that can be incorporated into glutathione or further metabolized to sulfate and taurine [1,3,89]. The transsulfuration pathway enzymes are pyridoxal-5-phosphate dependent [3,91]. This co-enzyme is the active form of pyridoxine. So, either folates, cobalamin, and pyridoxine are essential to keep normal homocysteine metabolism. The former two are coenzymes for the methylation pathway, the last one is coenzyme for the transsulfuration pathway [ 1,3,89,91 ]. 

Vitamin B plays important roles in cell metabolism. Vitamin B actually consists of eight chemically distinct biologically active agents that function as coenzymes. Pyridoxine, pyridoxal, and pyridoxamine or pyridoxine hydrochloride can all be called vitamin B6 as they are all converted to the active form. Pyridoxine is involved in the metabolism of amino acids and lipids. A vitamin B6-dependent enzyme model... 

FIGURE 12.3 Pridoxamine-PCDs as vitamin B6-dependent enzyme model. 

Vitamin B6 enzyme models that can catalyze five types of reactions - transamination, racemization, decarboxylation, P-elimination and replacement, and aldolase-type reactions - have been reviewed. There are also five approaches to construct the vitamin B6 enzyme models (i) vitamin B6 augmented with basic or chiral auxiliary functional groups (ii) vitamin B6 having an artificial binding site (iii) vitamin B6-surfactant systems (iv) vitamin B6-polypeptide systems (v) polymeric and dendrimeric vitamin B6 systems. These model systems show rate enhancement and some selectivity in vitamin B6-dependent reactions, but they are still primitive compared with the real enzymes. We expect to see improved reaction rates and selectivities in future generations of vitamin B6 enzyme models. An additional goal, which has not received ade-... 

Allenic amino acids belong to the classical suicide substrates for the irreversible mechanism-based inhibition of enzymes [5], Among the different types of allenic substrates used for enzyme inhibition [128, 129], the deactivation of vitamin B6 (pyr-idoxal phosphate)-dependent decarboxylases by a-allenic a-amino acids plays an important role (Scheme 18.45). In analogy with the corresponding activity of other /3,y-unsaturated amino acids [102,130], it is assumed that the allenic amino acid 139 reacts with the decarboxylase 138 to furnish the imine 140, which is transformed into a Michael acceptor of type 141 by decarboxylation or deprotonation. Subsequent attack of a suitable nucleophilic group of the active site then leads to inhibition of the decarboxylase by irreversible formation of the adduct 142 [131,132]. 

A group of enzymes which is particularly important in amino acid metabolism in the liver (and also in muscle) is the transaminases, (also called aminotransferases). These are vitamin B6 (pyridoxine) dependent enzymes which transfer an amino group from an amino acid to an oxo (keto) acid, thus ... 

It is conceivable that McArdle s patients need to pay greater attention to their vitamin B6 status than normal individuals. A compromised vitamin B6 status might be of even greater significance if McArdle s patients are more reliant on amino acid metabolism for muscle work—transaminases are PLP-dependent enzymes. Preliminary studies in our laboratory have established that McArdle s patients show differences in vitamin B6 metabolism and that they respond quickly and dramatically to short-term changes in vitamin B6 status (Beynon etal, 1995). Whether improvement of vitamin B6 status could enhance muscle performance remains to be seen. 

---