Pyruvate, synthesis from glucose

The acetyl CoA used for ACh synthesis in mammalian brain comes from pyruvate formed from glucose. It is unclear how the acetyl CoA, generally thought to be formed at the inner membrane of the mitochondria, accesses the cytoplasmic ChAT. This may also be a regulated, rate-limiting step. 

The processes involved in neurochemical transmission in a cholinergic neuron are shown in Figure 9.2. The initial substrates for the synthesis of acetylcholine are glucose and choline. Glucose enters the neuron by means of facilitated transport. There is some disagreement as to whether choline enters cells by active or facilitated transport. Pyruvate derived from glucose is transported into mitochondria and converted to acetylcoenzyme A (acetyl-CoA). The acetyl-CoA is transported back into the cytosol. With the aid of the enzyme choline acetyl-transferase, acetylcholine is synthesized from acetyl-CoA and choline. The acetylcholine is then transported into and stored within the storage vesicles by as yet unknown mechanisms. 

Fig. 1. Pathway of fatty acid synthesis from glucose in animal tissues. The key enzymes or enzyme systems involved are (1) pyruvate dehydrogenase, (2) pyruvate carboxylase, (3) citrate synthase, (4) citrate translocation system, (5) citrate cleavage enzyme, (6) acetyl-CoA carboxylase, (7) fatty acid synthetase, (8) 3-phosphoglyceraldehyde dehydrogenase, (9) malate dehydrogenase, (10) malic enzyme, (11) hexose monophosphate shunt.

Thiamine Thiamine Pyruvate dehydrogenase Fatty-acid synthesis from glucose phytanic... 

Biotin Biocytin Acetyl-CoA carboxylase pyruvate carboxylase Fatty-acid synthesis from glucose... 

Several of the B vitamins are essential for normal fatty-acid metabolism (Table 2). Pantothenic acid is a constituent of CoA and is thus required for numerous reactions of fatty acids. Niacin and riboflavin are necessary for the synthesis of oxidized and reduced NAD(P) and FAD, respectively. These compounds play essential roles in fatty-acid oxidation, synthesis, and elongation. Biotin is a constituent of acetyl-CoA carboxylase and pyruvate carboxylase, both of which are involved in the synthesis of fatty acids from glucose. Thiamine is required for activity of the pyruvate dehydrogenase complex, which also participates in fatty-acid synthesis from glucose. 

The net free energy change, AG°, for this conversion is —37.7 kj/mol. The consumption of a total of six nucleoside triphosphates drives this process forward. If glycolysis were merely reversed to achieve the net synthesis of glucose from pyruvate, the net reaction would be... 

There are two unusual aspects to the regulation of gluconeogenesis. The first step in the reaction, the formation of oxaloacetate from pyruvate, requires the presence of acetyl-CoA. This is a check to make sure that the TCA cycle is adequately fueled. If there s not enough acetyl-CoA around, the pyruvate is needed for energy and gluconeogenesis won t happen. However, if there s sufficient acetyl-CoA, the pyruvate is shifted toward the synthesis of glucose. 

The biosynthetic pathway to glucose described above allows the net synthesis of glucose not only from pyruvate but also from the four-, five-, and six-carbon intermediates of the citric acid cycle (Chapter 16). Citrate,... 

Seven glycolytic reactions are reversible and are used in the synthesis of glucose from lactate or pyruvate. However, three of the reactions are irreversible and must be circumvented by four alternate reactions that energetically favor the synthesis of glucose. These reactions, unique to gluconeogenesis, are described below. 

The first "roadblock" to overcome in the synthesis of glucose from pyruvate is the irreversible conversion in glycolysis of pyruvate to phosphoenolpyruvate (PEP) by pyruvate kinase. In gluconeogenesis, pyruvate is first carboxylated by pyruvate carboxylase to oxaloacetate (OAA), which is then converted to PEP by the action of PEP-carboxykinase (Figure 10.3). 

Figure 20-9 The glycolytic sequence. [The dashed arrows in the reverse direction indicate the steps in the synthesis of glucose from pyruvate (glyconeogenesis) that differ from those in glycolysis.]...

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