Bioenergetics and Metabolic Pathways

Free energy and high-energy phosphate compounds

Free energy change, written \Delta G, indicates whether a process is spontaneous and how much useful work it can deliver. Under standard conditions (pH 7, 1 M solutes) it is written \Delta G^{\circ\prime}, while the actual value in the cell depends on concentrations through \Delta G = \Delta G^{\circ\prime} + RT\ln Q, where Q is the reaction quotient built from product and substrate concentrations. A negative \Delta G marks an exergonic process, and an endergonic process with positive \Delta G can proceed only when it is coupled to an exergonic one. The term energy-requiring applies to transport that moves a solute against its gradient. Active transport and the Na^+/K^+ ATPase use ATP hydrolysis to pump ions uphill, so they are energy-requiring. Facilitated diffusion and simple diffusion move solutes down their gradient, with or without carriers, and need no energy input.

High-energy phosphate compounds store energy in phosphoanhydride or acyl phosphate bonds, whose hydrolysis releases a standard free energy of about -30 kJ/mol or more. Phosphoenolpyruvate and 1,3-bisphosphoglycerate are typical examples. AMP, which has only one phosphoester bond, has low phosphoryl transfer potential. Vitamin K is a lipid-soluble quinone and does not store phosphoryl energy.

The \Delta G^{\circ\prime} values of coupled reactions add. A strongly negative hydrolysis, such as that of PEP, can drive an unfavorable ATP synthesis from ADP, so the net \Delta G^{\circ\prime} is negative. Because \Delta G also depends on Q, a large ratio of product to substrate makes RT\ln Q positive and pushes \Delta G toward zero. For example, at 37^\circC, RT \approx 2.58 kJ/mol, so with Q = 0.1 the term RT\ln Q is about -5.9 kJ/mol.

For ATP hydrolysis in cells, Q = [\text{ADP}][P_i]/[\text{ATP}]. The actual \Delta G is therefore most negative when ATP is high and ADP and P_i are low. Comparing cell types, the one with the smallest Q has the most negative \Delta G for ATP hydrolysis.

A phosphoanhydride bond is a P–O–P linkage, found in ADP, ATP and pyrophosphate. A phosphoester bond, C–O–P, links phosphate to an alcohol or sugar carbon and is not a high-energy anhydride. Sugar bisphosphates such as fructose 1,6-bisphosphate contain only phosphoester bonds.

Biological power is the rate of ATP turnover multiplied by the energy released per mole. To convert, divide molecules by Avogadro's number to get moles, convert kcal to kJ or cal to J, and multiply so that the result is in J/s, which is W. For example, one ATP molecule turned over per second, releasing 12 kcal/mol, gives \dfrac{12000 \times 4.18}{6.023\times10^{23}} \approx 8.3\times10^{-20} W. Whole-body estimates then scale this value by the number of molecules and cells involved.

Glucose 6-phosphate metabolic branch point

Glucose 6-phosphate, formed from glucose by hexokinase or glucokinase, is a branch point that sends carbon into several pathways. In glycolysis it is isomerized to fructose 6-phosphate. For glycogen synthesis, phosphoglucomutase converts it to glucose 1-phosphate, which then forms UDP-glucose. In the pentose phosphate pathway it is oxidized to ribose 5-phosphate, the precursor of PRPP and therefore of purine and pyrimidine nucleotides. Glucose 6-phosphate is thus shared by glycolysis, nucleotide synthesis and glycogen synthesis.

The oxidative phase of the pentose phosphate pathway uses glucose 6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase. These reduce two NADP^+ to NADPH per glucose 6-phosphate, release one CO_2, and form ribulose 5-phosphate. The overall stoichiometry is glucose 6-phosphate + 2 NADP^+ + H_2O → ribulose 5-phosphate + 2 NADPH + 2 H^+ + CO_2.

Hexokinases I, II and III are allosterically inhibited by glucose 6-phosphate, which limits glucose phosphorylation when this intermediate accumulates. Glucokinase, which is hexokinase IV, is not inhibited by glucose 6-phosphate. It is regulated instead by the glucokinase regulatory protein, which binds and sequesters the enzyme in the nucleus.

Fatty acid oxidation energy yield

β-Oxidation of fatty acids removes two-carbon units as acetyl-CoA. Each cycle produces one FADH_2 and one NADH. Palmitic acid, a C16 fatty acid, requires seven cycles and yields eight acetyl-CoA, so it provides far more reducing equivalents than a six-carbon glucose molecule. The ATP yield per carbon is therefore higher for fatty acids than for glucose.

The reason is that fatty acid carbons are more reduced. They carry many C–H bonds and few C–O bonds, so oxidizing them releases more electrons into NADH and FADH_2. These carriers feed the electron transport chain, and the greater electron supply raises ATP production per carbon. Hence the statement that palmitic acid yields more ATP per carbon than glucose is true, and the higher reduction state of its carbons correctly explains it.