Arsenic poisoning: The toxicity of arsenic is due primarily to the inhibition by trivalent arsenic (arsenite) of enzymes such as the pyruvate dehydrogenase complex (PDHC), which require lipoic acid as a coenzyme (see p. 110). However, pentavalent arsenic (arsenate) can prevent net ATP and NADH production by glycolysis without inhibiting the pathway itself. It does so by competing with Pi as a substrate for glyceraldehyde 3-phosphate dehydrogenase, forming a complex that spontaneously hydrolyzes to form 3-phosphoglycerate (see Fig. 8.18). By bypassing the synthesis of and phosphate transfer from 1,3-BPG, the cell is deprived of energy usually obtained from the glycolytic pathway. [Note: Arsenate also competes with Pi binding to the F1 domain of ATP synthase (see p. 78), resulting in formation of ADP-arsenate that is rapidly hydrolyzed.] 3. 2,3-Bisphosphoglycerate synthesis in RBC: Some of the 1,3-BPG is converted to 2,3-BPG by the action of bisphosphoglycerate mutase (see Fig. 8.18). 2,3-BPG, which is found in only trace amounts in most cells, is present at high concentration in RBC and serves to increase O2 delivery (see p. 31). 2,3-BPG is hydrolyzed by a phosphatase to 3phosphoglycerate, which is also an intermediate in glycolysis (see Fig. 8.18). In the RBC, glycolysis is modified by inclusion of these shunt reactions.
G. 3-Phosphoglycerate synthesis and ATP production
When 1,3-BPG is converted to 3-phosphoglycerate, the high-energy phosphate group of 1,3-BPG is used to synthesize ATP from ADP (see Fig. 8.18). This reaction is catalyzed by phosphoglycerate kinase, which, unlike most other kinases, is physiologically reversible. Because two molecules of 1,3-BPG are formed from each glucose molecule, this kinase reaction replaces the two ATP molecules consumed by the earlier formation of glucose 6-phosphate and fructose 1,6-bisphosphate. [Note: This reaction is an example of substrate-level phosphorylation, in which the energy needed for the production of a high-energy phosphate comes from a substrate rather than from the ETC (see J. below and p. 113 for other examples).]
H. Phosphate group shift
The shift of the phosphate group from carbon 3 to carbon 2 of phosphoglycerate by phosphoglycerate mutase is freely reversible.
I. 2-Phosphoglycerate dehydration
The dehydration of 2-phosphoglycerate by enolase redistributes the energy within the substrate, forming phosphoenolpyruvate (PEP), which contains a high-energy enol phosphate (see Fig. 8.18). The reaction is reversible, despite the high-energy nature of the product. [Note: Fluoride inhibits enolase, and water fluoridation reduces lactate production by mouth bacteria, decreasing dental caries (see p. 405).]
J. Pyruvate synthesis and ATP production
The conversion of PEP to pyruvate, catalyzed by pyruvate kinase (PK), is the third irreversible reaction of glycolysis. The high-energy enol phosphate in PEP is used to synthesize ATP from ADP and is another example of substrate-level phosphorylation (see Fig. 8.18).
1.