It serves as a precursor to many molecules, such as lactate, alanine, and oxaloacetate. Glycolysis precedes lactic acid fermentation; the pyruvate made in the former process serves as the prerequisite for the lactate made in the latter process. Lactic acid fermentation is the primary source of ATP in animal tissues with low metabolic requirements and little to no mitochondria.
In erythrocytes, lactic acid fermentation is the sole source of ATP, as they lack mitochondria and mature red blood cells have little demand for ATP. Another part of the body that relies entirely or almost entirely on anaerobic glycolysis is the eye's lens, which is devoid of mitochondria, as their presence would lead to light scattering. Though skeletal muscles prefer to catalyze glucose into carbon dioxide and water during heavy exercise where oxygen is inadequate, the muscles simultaneously undergo anaerobic glycolysis and oxidative phosphorylation.
The amount of glucose available for the process regulates glycolysis, which becomes available primarily in two ways: regulation of glucose reuptake or regulation of the breakdown of glycogen.
Glucose transporters GLUT transport glucose from the outside of the cell to the inside. Cells containing GLUT can increase the number of GLUT in the cell's plasma membrane from the intracellular matrix, therefore increasing the uptake of glucose and the supply of glucose available for glycolysis. There are five types of GLUTs. GLUT3 is present in neurons.
GLUT4 is in adipocytes, heart, and skeletal muscle. GLUT5 specifically transports fructose into cells. Another form of regulation is the breakdown of glycogen. Cells can store extra glucose as glycogen when glucose levels are high in the cell plasma. Conversely, when levels are low, glycogen can be converted back into glucose. Two enzymes control the breakdown of glycogen: glycogen phosphorylase and glycogen synthase.
As described before, many enzymes are involved in the glycolytic pathway by converting one intermediate to another. Control of these enzymes, such as hexokinase, phosphofructokinase, glyceraldehydephosphate dehydrogenase, and pyruvate kinase, can regulate glycolysis.
The amount of oxygen available can also regulate glycolysis. The mechanisms responsible for this effect include allosteric regulators of glycolysis enzymes such as hexokinase.
Still, this effect is not universal in oxidative tissue, such as pancreatic cells. Another mechanism for controlling glycolytic rates is transcriptional control of glycolytic enzymes. Altering the concentration of key enzymes allows the cell to change and adapt to alterations in hormonal status. For example, increasing glucose and insulin levels can increase hexokinase and pyruvate kinase activity, therefore increasing the production of pyruvate.
Fructose 2,6-bisphosphate is an allosteric regulator of PFK High levels of fructose 2,6-bisphosphate increase the activity of PFK This results in its carbon-oxygen double bond being reduced to a carbon-oxygen single bond with the addition of a hydrogen atom. The result is the molecule lactate. From the lactate product, lactic acid can be formed, which causes the muscle fatigue that accompanies strenuous workouts where oxygen becomes deficient.
There is another way that the NADH molecule can be re-oxidized. Anaerobic conditions in yeast convert pyruvate to carbon dioxide and ethanol. This occurs with the help of the enzyme pyruvate decarboxylase which removes a carbon dioxide molecule from the pyruvate to yield an acetaldehyde. The acetaldehyde is then reduced by the enzyme alcohol dehydrogenase which transfers the hydrogen from NADH to the acetaldehyde to yield NAD and ethanol.
This enzyme is not found in humans. This description of the glycolytic pathway has stood unchallenged for more than six decades. However, beginning in the s, studies in the fields of both muscle and brain energy metabolism have indicated that lactate is not a useless product of anaerobic glycolysis, but rather a potential important player in energy metabolism in these tissues and possibly others. The present chapter describes the key biochemical and physiological data both from the early days of research on carbohydrate metabolism and those gathered over the past three decades that have challenged the original, dogmatic layout of the glycolytic pathway.
Hopefully, this chapter will spur biochemists, physiologists and neuroscientists to consider the reconfiguration of glycolysis as proposed here and elsewhere.
This usually follows with the qualification that under aerobic conditions, the glycolytic pathway leads up to the tricarboxylic acid cycle TCA and the electron transfer chain ETC , the two biochemical processes responsible for capturing the majority of energy contained in glucose. In contrast, under anaerobic conditions, such as those existing in working muscles, pyruvate is reduced to lactate.
The elucidation of the glycolytic pathway was completed in , thanks mainly to studies by Meyerhof, Embeden, Parnas, Warburg, Neuberg and Gerty and Carl Cori. It has been the first biochemical pathway to be elucidated, opening the door for future such puzzle solutions and to the field of biochemistry as we know it today.
For those who are interested in refreshing their knowledge about the ten or so enzymatic steps of glycolysis and the coenzymes, substrates and products of these steps, any recent biochemistry textbook will do see also Figure 1A and B. Nevertheless, despite some uncertainties that have led to unproven assumptions about the role and function of the two alternative glycolytic end products, pyruvate and lactate, the glycolytic pathway has been accepted as originally proposed in The first nine reactions of glycolysis are summarily listed in Figure 1A.
These nine reactions end with pyruvate, the product suggested as the substrate for the mitochondrial TCA cycle under aerobic conditions. Since under anaerobic conditions mitochondrial respiration is halted, a 10th reaction was added to the original glycolytic pathway formulation where pyruvate is reduced to lactate by lactate dehydrogenase LDH, Figure 1B.
Hence, under anaerobic conditions, glycolysis was postulated to reach a dead-end point. A schematic illustration of the classic glycolytic pathway as originally perceived both under aerobic A and anaerobic B conditions.
Under aerobic conditions, pyruvate is assigned as the end-product of the pathway, while under anaerobic conditions, lactate is the end product. This is one of the main drawbacks of the classical aerobic glycolytic pathway. In , Brooks [ 3 ] published results showing that during prolonged exercise of skeletal muscle, lactate is both produced glycolytically and consumed oxidatively.
The finding that activated brain tissue produces lactate [ 5 ] should not have been that surprising, since it indicates that activated brain tissue resorts to non-oxidative energy production similar to activated muscle tissue.
However, the findings by both Brooks [ 3 ] and Schurr et al. Consequently, one must wonder why it took over four decades to produce results that challenge the dogma of two separate glycolytic pathways, aerobic and anaerobic. Alternatively, could it be that earlier findings in both muscle and brain tissues had already pointed at the possibility that lactate is more than just a useless end product of glycolysis, but for obscure reasons were ignored?
In a review article, Schurr [ 22 ] examined the history of carbohydrate energy metabolism from its earlier stages at the end of the nineteenth century to the elucidation of the glycolytic pathway in and beyond. That review has unearthed some intriguing findings, both about the scientists who were leading the field at the time and the interpretation of their own research data. The scientific debate that ensued following the publications by Brooks [ 3 ] and Schurr et al. Sour milk, where lactic acid lactate was first discovered, sets the tone for what has become for years to come the negative trademark of this monocarboxylate.
Once found in working muscle, lactate was immediately blamed for muscle fatigue and rigor. As early as , Fletcher [ 24 ] demonstrated that lactic acid he used 0. The higher the lactic acid concentration, the quicker the rigor mortis sets in. Moreover, Fletcher and Hopkins [ 25 ] have shown that in the presence of oxygen, the survival of the excised muscle was prolonged and so did the acceleration of the disposal of lactate from it.
These researchers highlighted the recognition that the body has the means to rid itself from muscular lactate and that there is ample evidence that such disposal is most efficient under oxidative conditions. Thus, the dogma of lactate as a muscular product responsible for fatigue and rigor, one that aerobic conditions enhance its disposal, was already well entrenched among scientists at the beginning of the twentieth century.
It is still entrenched today among athletes and their coaches. Hill [ 7 , 8 ] went even further than Fletcher by suggesting that the role of oxygen in muscle contracture is twofold, to decrease the duration of heat production and to remove lactate from it. Hill argued that the measured heat production of lactate oxidation was much lower than the calculated value of its complete combustion.
However, under anaerobic conditions, only 2 mol of ATP can be produced. Aerobic glycolysis occurs in 2 steps.
The first occurs in the cytosol and involves the conversion of glucose to pyruvate with resultant production of NADH. This process alone generates 2 molecules of ATP.
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