Editing Glycolysis (section)

== Post-glycolysis processes ==
The overall process of glycolysis is:

:Glucose + 2 NAD<sup>+</sup> + 2 ADP + 2 P<sub>i</sub> → 2 Pyruvate + 2 NADH + 2 H<sup>+</sup> + 2 ATP + 2 H<sub>2</sub>O

If glycolysis were to continue indefinitely, all of the NAD<sup>+</sup> would be used up, and glycolysis would stop. To allow glycolysis to continue, organisms must be able to oxidize NADH back to NAD<sup>+</sup>. How this is performed depends on which external electron acceptor is available.

===Anoxic regeneration of NAD<sup>+</sup>===
{{Unreferenced section|date=June 2022}}
One method of doing this is to simply have the pyruvate do the oxidation; in this process, pyruvate is converted to [[lactic acid|lactate]] (the [[conjugate base]] of lactic acid) in a process called [[lactic acid fermentation]]:

:Pyruvate + NADH + H<sup>+</sup> → Lactate + NAD<sup>+</sup>

This process occurs in the [[bacterium|bacteria]] involved in making [[yogurt]] (the lactic acid causes the milk to curdle). This process also occurs in animals under hypoxic (or partially anaerobic) conditions, found, for example, in overworked muscles that are starved of oxygen. In many tissues, this is a cellular last resort for energy; most animal tissue cannot tolerate anaerobic conditions for an extended period of time.

Some organisms, such as yeast, convert NADH back to NAD<sup>+</sup> in a process called [[ethanol fermentation]].  In this process, the pyruvate is converted first to acetaldehyde and carbon dioxide, and then to ethanol.

Lactic acid fermentation and ethanol fermentation can occur in the absence of oxygen.  This anaerobic fermentation allows many single-cell organisms to use glycolysis as their only energy source.

Anoxic regeneration of NAD<sup>+</sup> is only an effective means of energy production during short, intense exercise in vertebrates, for a period ranging from 10 seconds to 2 minutes during a maximal effort in humans. (At lower exercise intensities it can sustain muscle activity in [[Mammalian diving reflex|diving animals]], such as seals, whales and other aquatic vertebrates, for very much longer periods of time.) Under these conditions NAD<sup>+</sup> is replenished by NADH donating its electrons to pyruvate to form lactate. This produces 2 ATP molecules per glucose molecule, or about 5% of glucose's energy potential (38 ATP molecules in bacteria). But the speed at which ATP is produced in this manner is about 100 times that of oxidative phosphorylation. The pH in the cytoplasm quickly drops when hydrogen ions accumulate in the muscle, eventually inhibiting the enzymes involved in glycolysis.

The burning sensation in muscles during hard exercise can be attributed to the release of hydrogen ions during the shift to glucose fermentation from glucose oxidation to carbon dioxide and water, when aerobic metabolism can no longer keep pace with the energy demands of the muscles. These hydrogen ions form a part of lactic acid. The body falls back on this less efficient but faster method of producing ATP under low oxygen conditions. This is thought to have been the primary means of energy production in earlier organisms before oxygen reached high concentrations in the atmosphere between 2000 and 2500 million years ago, and thus would represent a more ancient form of energy production than the aerobic replenishment of NAD<sup>+</sup> in cells.

The liver in mammals gets rid of this excess lactate by transforming it back into pyruvate under aerobic conditions; see [[Cori cycle]].

Fermentation of pyruvate to lactate is sometimes also called "anaerobic glycolysis", however, glycolysis ends with the production of pyruvate regardless of the presence or absence of oxygen.

In the above two examples of fermentation, NADH is oxidized by transferring two electrons to pyruvate.  However, anaerobic bacteria use a wide variety of compounds as the terminal electron acceptors in [[cellular respiration]]: nitrogenous compounds, such as nitrates and nitrites; sulfur compounds, such as sulfates, sulfites, sulfur dioxide, and elemental sulfur; carbon dioxide; iron compounds; manganese compounds; cobalt compounds; and uranium compounds.

===Aerobic regeneration of NAD<sup>+</sup> and further catabolism of pyruvate===
In [[aerobic organism|aerobic]] [[eukaryote]]s, a complex mechanism has developed to use the oxygen in air as the final electron acceptor, in a process called [[oxidative phosphorylation]]. [[aerobic organism|Aerobic]] [[prokaryotes]], which lack mitochondria, use a variety of [[Oxidative phosphorylation#Prokaryotic electron transport chains|simpler mechanisms]].
* Firstly, the  [[Nicotinamide adenine dinucleotide|NADH + H<sup>+</sup>]] generated by glycolysis has to be transferred to the mitochondrion to be oxidized, and thus to regenerate the NAD<sup>+</sup> necessary for glycolysis to continue. However the inner mitochondrial membrane is impermeable to NADH and NAD<sup>+</sup>.<ref name=stryer5>{{cite book | vauthors = Stryer L | title = Biochemistry |chapter= Oxidative phosphorylation. |edition= Fourth |location= New York |publisher= W.H. Freeman and Company|date= 1995 |pages= 537–549 |isbn= 0-7167-2009-4 }}</ref>  Use is therefore made of two "shuttles" to transport the electrons from NADH across the mitochondrial membrane. They are the [[malate-aspartate shuttle]] and the [[glycerol phosphate shuttle]]. In the former the electrons from NADH are transferred to cytosolic [[Oxaloacetic acid|oxaloacetate]] to form [[Malic acid|malate]]. The malate then traverses the inner mitochondrial membrane into the mitochondrial matrix, where it is reoxidized by NAD<sup>+</sup> forming intra-mitochondrial oxaloacetate and NADH. The oxaloacetate is then re-cycled to the cytosol via its conversion to aspartate which is readily transported out of the mitochondrion. In the glycerol phosphate shuttle electrons from cytosolic NADH are transferred to [[dihydroxyacetone]] to form [[glycerol-3-phosphate]] which readily traverses the outer mitochondrial membrane. Glycerol-3-phosphate is then reoxidized to dihydroxyacetone, donating its electrons to [[Flavin adenine dinucleotide|FAD]] instead of NAD<sup>+</sup>.<ref name=stryer5 /> This reaction takes place on the inner mitochondrial membrane, allowing FADH<sub>2</sub> to donate its electrons directly to coenzyme Q ([[ubiquinone]]) which is part of the [[electron transport chain]] which ultimately transfers electrons to molecular oxygen {{chem2|O2}}, with the formation of water, and the release of energy eventually captured in the form of [[Adenosine triphosphate|ATP]].
* The glycolytic end-product, pyruvate (plus NAD<sup>+</sup>) is converted to [[acetyl-CoA]], {{chem2|CO2}} and NADH + H<sup>+</sup> within the [[mitochondria]] in a process called [[pyruvate decarboxylation]].
* The resulting acetyl-CoA enters the [[citric acid cycle]] (or Krebs Cycle), where the acetyl group of the acetyl-CoA is converted into carbon dioxide by two decarboxylation reactions with the formation of yet more intra-mitochondrial NADH + H<sup>+</sup>.
* The intra-mitochondrial NADH + H<sup>+</sup> is oxidized to NAD<sup>+</sup> by the [[electron transport chain]], using oxygen as the final electron acceptor to form water.  The energy released during this process is used to create a hydrogen ion (or proton) gradient across the [[inner membrane of the mitochondrion]].
* Finally, the proton gradient is used to produce about 2.5 [[Adenosine triphosphate|ATP]] for every NADH + H<sup>+</sup> oxidized in a process called [[oxidative phosphorylation]].<ref name=stryer5 />

===Conversion of carbohydrates into fatty acids and cholesterol===
The pyruvate produced by glycolysis is an important intermediary in the conversion of carbohydrates into [[fatty acids]] and [[cholesterol]].<ref name=stryer2>{{cite book | vauthors = Stryer L | title = Biochemistry |chapter= Fatty acid metabolism. |edition= Fourth |location= New York |publisher= W.H. Freeman and Company|date= 1995 |pages= 603–628 |isbn= 0-7167-2009-4 }}</ref> This occurs via the conversion of pyruvate into [[acetyl-CoA]] in the [[mitochondrion]]. However, this acetyl CoA needs to be transported into cytosol where the synthesis of fatty acids and cholesterol occurs. This cannot occur directly. To obtain cytosolic acetyl-CoA, [[Citric acid|citrate]] (produced by the condensation of acetyl CoA with [[Oxaloacetic acid|oxaloacetate]]) is removed from the [[citric acid cycle]] and carried across the inner mitochondrial membrane into the [[cytosol]].<ref name=stryer2 /> There it is cleaved by [[ATP citrate lyase]] into acetyl-CoA and oxaloacetate. The oxaloacetate is returned to mitochondrion as malate (and then back into oxaloacetate to transfer more acetyl-CoA out of the mitochondrion). The cytosolic acetyl-CoA can be carboxylated by [[acetyl-CoA carboxylase]] into [[Malonyl-CoA|malonyl CoA]], the first committed step  in the  [[Fatty acid synthesis|synthesis of fatty acids]], or it can be combined with [[acetoacetyl-CoA]] to form 3-hydroxy-3-methylglutaryl-CoA ([[HMG-CoA]]) which is the rate limiting step controlling the [[Mevalonate pathway|synthesis of cholesterol]].<ref name=stryer4>{{cite book | vauthors = Stryer L | title = Biochemistry |chapter= Biosynthesis of membrane lipids and steroids. |edition= Fourth |location= New York |publisher= W.H. Freeman and Company|date= 1995 |pages= 691–707 |isbn= 0-7167-2009-4 }}</ref> Cholesterol can be used as is, as a structural component of cellular membranes, or it can be used to synthesize the [[Steroid#Steroidogenesis|steroid hormones]], [[Bile acids|bile salts]], and [[vitamin D]].<ref name=voet /><ref name=stryer2 /><ref name=stryer4 />

===Conversion of pyruvate into oxaloacetate for the citric acid cycle===
Pyruvate molecules produced by glycolysis are [[active transport|actively transported]] across the inner [[Mitochondrion|mitochondrial]] membrane, and into the matrix where they can either be [[Redox|oxidized]] and combined with [[coenzyme A]] to form {{chem2|CO2}}, acetyl-CoA, and NADH,<ref name=voet /> or they can be [[carboxylated]] (by [[pyruvate carboxylase]]) to form [[oxaloacetate]]. This latter reaction "fills up" the amount of oxaloacetate in the citric acid cycle, and is therefore an [[anaplerotic reaction]] (from the Greek meaning to "fill up"), increasing the cycle's capacity to metabolize acetyl-CoA when the tissue's energy needs (e.g. in [[Cardiac muscle|heart]] and [[Skeletal striated muscle|skeletal muscle]]) are suddenly increased by activity.<ref name=stryer3>{{cite book | vauthors = Stryer L | title = Biochemistry |chapter= Citric acid cycle. |edition= Fourth |location= New York |publisher= W.H. Freeman and Company|date= 1995 |pages= 509–527, 569–579, 614–616, 638–641, 732–735, 739–748, 770–773 |isbn= 0-7167-2009-4 }}</ref>
In the [[citric acid cycle]] all the intermediates (e.g. citrate, iso-citrate, alpha-ketoglutarate, succinate, fumarate, malate and oxaloacetate) are regenerated during each turn of the cycle. Adding more of any of these intermediates to the mitochondrion therefore means that that additional amount is retained within the cycle, increasing all the other intermediates as one is converted into the other. Hence the addition of oxaloacetate greatly increases the amounts of all the citric acid intermediates, thereby increasing the cycle's capacity to metabolize acetyl CoA, converting its acetate component into {{chem2|CO2}} and water, with the release of enough energy to form 11 [[Adenosine triphosphate|ATP]] and 1 [[Guanosine triphosphate|GTP]] molecule for each additional molecule of acetyl CoA that combines with oxaloacetate in the cycle.<ref name=stryer3 />

To cataplerotically remove oxaloacetate from the citric cycle, [[malate]] can be transported from the mitochondrion into the cytoplasm, decreasing the amount of oxaloacetate that can be regenerated.<ref name=stryer3 /> Furthermore, citric acid intermediates are [[Citric acid cycle#Citric acid cycle intermediates serve as substrates for biosynthetic processes|constantly used to form a variety of substances such as the purines, pyrimidines and porphyrins]].<ref name=stryer3 />