Dihydroxyacetone phosphate pathway

Agranofl, B. W., Hajra, A. K. The acyl dihydroxyacetone phosphate pathway for glycerolipid biosynthesis in mouse liver and Ehrlich ascites tumor cells. Proc. Natl. Acad. Sci. U.S. 68, 411-415 (1971). 

The major pathways for triacylglycerol synthesis are shown in Fig. 11.17. The formation of phos-phatidic acid by the glycerol phosphate pathway or the dihydroxyacetone phosphate pathway has already been discussed (Section 11.2.11). In addition, see reviews by Gurr (1980) and O Doherty (1978). Phosphatidic add can also be formed from... 

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... 

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]. 

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. 

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). 

Figure 17-2. The pathway of glycolysis. ( ,—P, HOPOj " .inhibition.) At asterisk Carbon atoms 1-3 of fructose bisphosphateform dihydroxyacetone phosphate, whereas carbons 4-6 form glyceraldehyde 3-phosphate. The term "bis-," as in bisphosphate, indicates that the phosphate groups are separated, whereas diphosphate, as in adenosine diphosphate, indicates that they are joined.

Figure 11.2 Pathway for conversion of fructose to acetyl-CoA. The enzyme fructokinase phosphorylates fructose to form fructose 1-phosphate. (The enzyme is present only in the liver.) Fructose 1-phosphate is cleaved by aldolase to form glyceraldehyde and dihydroxyacetone phosphate. Glyceraldehyde is phos-phorylated to form glyceraldehyde 3-phosphate, catalysed by the enzyme triokinase. Dihydroxyacetone phosphate is converted to glyceraldehyde 3-phosphate, catalysed by the isomerase. Glyceraldehyde 3-phosphate is converted to pyruvate by the glycolytic reactions (Chapter 6).

Tautomerism occurs elsewhere in the glycolytic pathway (see Section 15.2). The transformation of glyceraldehyde 3-phosphate into dihydroxyacetone phosphate involves two such keto-enol tautomerisms, and... 

Both the aldol and reverse aldol reactions are encountered in carbohydrate metabolic pathways in biochemistry (see Chapter 15). In fact, one reversible transformation can be utilized in either carbohydrate biosynthesis or carbohydrate degradation, according to a cell s particular requirement. o-Fructose 1,6-diphosphate is produced during carbohydrate biosynthesis by an aldol reaction between dihydroxyacetone phosphate, which acts as the enolate anion nucleophile, and o-glyceraldehyde 3-phosphate, which acts as the carbonyl electrophile these two starting materials are also interconvertible through keto-enol tautomerism, as seen earlier (see Section 10.1). The biosynthetic reaction may be simplihed mechanistically as a standard mixed aldol reaction, where the nature of the substrates and their mode of coupling are dictated by the enzyme. The enzyme is actually called aldolase. 

In Box 10.4 we saw that an aldol-like reaction could be used to rationalize the biochemical conversion of dihydroxyacetone phosphate (nucleophile) and glyceraldehyde 3-phosphate (electrophile) into fructose 1,6-diphosphate by the enzyme aldolase during carbohydrate biosynthesis. The reverse reaction, used in the glycolytic pathway for carbohydrate metabolism, was formulated as a reverse aldol reaction. 

The main group of aldolases from the biocatalytic point of view is, arguably, the one that uses dihydroxyacetone phosphate (DHAP) as donor. Here, we will concentrate on that appHcations in which DHAP-dependent aldolase are part of a multi-enzyme system or, alternatively, on those in which the aldolase-catalyzed reaction is key in a multi-step synthetic pathway. 

Although we have described metabolic transformations in plant cells in terms of individual pathways, these pathways interconnect so completely that we should instead consider pools of metabolic intermediates shared among these pathways and connected by readily reversible reactions (Fig. 20-37). One such metabolite pool includes the hexose phosphates glucose 1-phosphate, glucose 6-phosphate, and fructose 6-phosphate a second includes the 5-phosphates of the pentoses ri-bose, ribulose, and xylulose a third includes the triose phosphates dihydroxyacetone phosphate and glycer-aldehyde 3-phosphate. Metabolite fluxes through these... 

FIGURE 21-21 Glyceroneogenesis. The pathway is essentially an abbreviated version of gluconeogenesis, from pyruvate to dihydroxyacetone phosphate (DHAP), followed by conversion of DHAP to glycerol 3-phosphate, which is used for the synthesis of triacylglycerol. 

Write the sequence of steps and the net reaction for the biosynthesis of phosphatidylcholine by the salvage pathway from oleate, palmitate, dihydroxyacetone phosphate, and choline. Starting from these precursors, what is the cost (in number of ATPs) of the synthesis of phosphatidylcholine by the salvage pathway ... 

Triose phosphate isomerase interconverts dihydroxyacetone phosphate and glyceraldehyde 3-phosphate (see Figure 8.16). Dihydroxyacetone phosphate must be isomerized to glyceraldehyde 3-phosphate for further metabolism by the glycolytic pathway. This isomerization results in the net production of two molecules of glyceraldehyde 3-phosphate from the cleavage products of fructose 1,6-bisphosphate. 

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