Dihydroxyacetone-1-phosphate

Bischofberger, N, Waldmann, H, Saito, T, Simon, E S, Lees, W, Bednarski, M D, Whitesides, G M, Synthesis of analogues of 1,3-dihydroxyacetone phosphate and glyceraldehyde 3-phosphate for use in studies of fructose-1,6-diphosphate aldolase, J. Org. Chem., 53, 3457-3465, 1988. 

The (R,S)-E-diastereomer of 2,4 3,5-bis(cyclicphosphoramidate) (21) was formed when the bis(cyclicphosphorochloridate) (22) was treated with piperidine and triethylamine. The X-ray analysis of product (24) is referred to in Chapter 22. Analogues (23) - (27) of 1,3-dihydroxyacetone phosphate have been prepared as potential... 

NAD(P)+ from the diet is first hydrolysed to a mixture of nicotinic acid and nicotinamide. Nicotinic acid can then be transformed into nicotinamide and then to NAD(P)+ in the body. These dinucleotides are de novo synthesised by bacteria and some plants from aspartic acid and 1,3-dihydroxyacetone phosphate (glycerone phosphate). Quinolinic acid is an intermediate. It arises from tryptophan in some microorganisms and in animals. 

Glycerol (propane-l,2,3-triol) mainly occurs in foods in theform of triacylglycerols, and many other lipids (glyceroKpids). Glycerol is also produced as a byproduct of alcoholic fermentation (also in alkaline media together with acetic acid salts) by reduction of the intermediate 1,3-dihydroxyacetone phosphate via glycerol 3-phosphate. 

Further steps m glycolysis use the d glyceraldehyde 3 phosphate formed m the aldolase catalyzed cleavage reaction as a substrate Its coproduct dihydroxyacetone phosphate is not wasted however The enzyme triose phosphate isomerase converts dihydroxyacetone phosphate to d glyceraldehyde 3 phosphate which enters the glycol ysis pathway for further transformations... 

Suggest a reasonable structure for the intermediate in the con ] version of dihydroxyacetone phosphate to o glyceraldehyde 3 phosphate J... 

There are two distinct groups of aldolases. Type I aldolases, found in higher plants and animals, require no metal cofactor and catalyze aldol addition via Schiff base formation between the lysiae S-amino group of the enzyme and a carbonyl group of the substrate. Class II aldolases are found primarily ia microorganisms and utilize a divalent ziac to activate the electrophilic component of the reaction. The most studied aldolases are fmctose-1,6-diphosphate (FDP) enzymes from rabbit muscle, rabbit muscle adolase (RAMA), and a Zn " -containing aldolase from E. coli. In vivo these enzymes catalyze the reversible reaction of D-glyceraldehyde-3-phosphate [591-57-1] (G-3-P) and dihydroxyacetone phosphate [57-04-5] (DHAP). 

The chemical reaction catalyzed by triosephosphate isomerase (TIM) was the first application of the QM-MM method in CHARMM to the smdy of enzyme catalysis [26]. The study calculated an energy pathway for the reaction in the enzyme and decomposed the energetics into specific contributions from each of the residues of the enzyme. TIM catalyzes the interconversion of dihydroxyacetone phosphate (DHAP) and D-glyceraldehyde 3-phosphate (GAP) as part of the glycolytic pathway. Extensive experimental studies have been performed on TIM, and it has been proposed that Glu-165 acts as a base for deprotonation of DHAP and that His-95 acts as an acid to protonate the carbonyl oxygen of DHAP, forming an enediolate (see Fig. 3) [58]. 

Figure 3 A possible mechanism for the isomerization of dihydroxyacetone phosphate (DHAP) to D glyceraldehyde 3 phosphate (GAP) by the enzyme triosephosphate isomerase (TIM). The general acid (Glu 165) and general base (His 95) are shown.

A non-linear regression analysis is employed using die Solver in Microsoft Excel spreadsheet to determine die values of and in die following examples. Example 1-5 (Chapter 1) involves the enzymatic reaction in the conversion of urea to ammonia and carbon dioxide and Example 11-1 deals with the interconversion of D-glyceraldehyde 3-Phosphate and dihydroxyacetone phosphate. The Solver (EXAMPLEll-l.xls and EXAMPLEll-3.xls) uses the Michaehs-Menten (MM) formula to compute v i- The residual sums of squares between Vg(,j, and v j is then calculated. Using guessed values of and the Solver uses a search optimization technique to determine MM parameters. The values of and in Example 11-1 are ... 

Dihydroxyacetone phosphate is of course an intermediate in glycolysis. D-Gly-ceraldehyde can be phosphorylated by triose kinase in the presence of ATP to form D-glyceraldehyde-3-phosphate, another glycolytic intermediate. 

One of the steps in the biological pathway for carbohydrate metabolism is the conversion of fructose 1,6-bisphosphate into dihydroxyacetone phosphate and glyceraldehyde 3-phosphate. Propose a mechanism for the transformation. 

The fatty acids released on triacylglycerol hydrolysis are transported to mitochondria and degraded to acetyl CoA, while the glycerol is carried to the liver for further metabolism. In the liver, glycerol is first phosphorylated by reaction with ATP. Oxidation by NAD+ then yields dihydroxyacetone phosphate (DHAP), which enters the carbohydrate metabolic pathway. We ll discuss this carbohydrate pathway in more detail in Section 29.5. 

Step 3 of Figure 29.3 Alcohol Oxidation The /3-hydroxyacyl CoA from step 2 is oxidized to a /3-ketoacyl CoA in a reaction catalyzed by one of a family of L-3-hydroxyacyl-CoA dehydrogenases, which differ in substrate specificity according to the chain length of the acyl group. As in the oxidation of sn-glycerol 3-phosphate to dihydroxyacetone phosphate mentioned at the end of Section 29.2, this alcohol oxidation requires NAD+ as a coenzyme and yields reduced NADH/H+ as by-product. Deprotonation of the hydroxyl group is carried out by a histidine residue at the active site. 

Fructose 1,6-bisphosphate undergoes ring opening and is cleaved by a retro-aldol reaction into glyceraldehyde 3-phosphate and dihydroxyacetone phosphate (DHAP). 

Step 4 of Figure 29.7 Cleavage Fructose 1,6-bisphosphate is cleaved in step 4 into two 3-carbon pieces, dihydroxyacetone phosphate (DHAP) and glyceraldehvde 3-phosphate (GAP). The bond between C3 and C4 of fructose 1,6-bisphosphate... 

Figure 29.9 Mechanism of step 4 in Figure 29.7, the cleavage of fructose 1,6-bisphosphate to yield glyceraldehyde 3-phosphate and dihydroxyacetone phosphate.

Reduction of the acyl phosphate gives glyceraldehyde 3-phosphate, which Q undergoes keto-enol tautomerization to yield dihydroxyacetone phosphate. 

Glyceraldehyde 3-phosphate and dihydroxyacetone phosphate join together in an aldol reaction to give fructose 1.6-bisphosphate. 

Due to mechanistic requirements, most of these enzymes are quite specific for the nucleophilic component, which most often is dihydroxyacetone phosphate (DHAP, 3-hydroxy-2-ox-opropyl phosphate) or pyruvate (2-oxopropanoate), while they allow a reasonable variation of the electrophile, which usually is an aldehyde. Activation of the donor substrate by stereospecific deprotonation is either achieved via imine/enamine formation (type 1 aldolases) or via transition metal ion induced enolization (type 2 aldolases mostly Zn2 )2. The approach of the aldol acceptor occurs stereospecifically following an overall retention mechanism, while facial differentiation of the aldehyde is responsible for the relative stereoselectivity. 

Table t. Products from Complementary Aldolase Catalyzed Additions of Dihydroxyacetone Phosphate to Simple Aldehydes... 

D-Sorbose Sugar Phosphates by Enzymatic Addition of Dihydroxyacetone Phosphate to Aldehydes Typical Procedure8 ... 

Dihydroxyacetone phosphate, 210 Dimethyl ether, heterolytic cleavage, 47,48, 53... 

Another pathway is the L-glycerol 3-phosphate shuttle (Figure 11). Cytosolic dihydroxyacetone phosphate is reduced by NADFl to s.n-glycerol 3-phosphate, catalyzed by s,n-glycerol 3-phosphate dehydrogenase, and this is then oxidized by s,n-glycerol 3-phosphate ubiquinone oxidoreductase to dihydroxyacetone phosphate, which is a flavoprotein on the outer surface of the inner membrane. By this route electrons enter the respiratory chain.from cytosolic NADH at the level of complex III. Less well defined is the possibility that cytosolic NADH is oxidized by cytochrome bs reductase in the outer mitochondrial membrane and that electrons are transferred via cytochrome b5 in the endoplasmic reticulum to the respiratory chain at the level of cytochrome c (Fischer et al., 1985). 

---