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Glycolysis can be divided into two parts, the preparative phase, which requires two ATP, and the energy producing phase, which produces NADH and ATP. The net result of glucose oxidation through glycolysis is twoATP, twoNADH and twopyruvate. Briefly, the process of glycolysis starts with the phosphorylation of a glucose molecule (six-carbon sugar). The addition of a phosphate grouptraps the glucose in the cell where it will undergo isomerization to fructose 6-phosphate and further phosphorylation to fructose 1,6-bisphosphate. From here, fructose 1,6-bisphosphate is cleaved by aldolase B into twothree-carbon compounds, which will ultimately produce two pyruvate. Under aerobic conditions, the pyruvate will enter the mitochondria and be oxidized to acetyl-CoA, which will enter the TCA cycle. When oxygen is limited or energy demands exceed oxygen delivery for ATP, the cell will rely on anaerobic glycolysis. In this case, lactate dehydrogenase will oxidize the NADH generated from glycolysis by reducing cytosolic pyruvate to lactate. Under these conditions oxygen is not required to reoxidize NADH, and therefore the process is referred to as anaerobic. The energy produced through this process is much less than through aerobic oxidation and therefore less favorable (figure 4.1).
Regulation of glycolysis
Glycolysis in the liver has three primary regulated and irreversible steps (figure 4.1).
Glucokinase: Glucose to glucose 6-phosphate
In the liver, glucose is taken up through an insulin-independent process mediated by GLUT2 transporters. Following this, glucose must be phosphorylated to be trapped in the cell. The phosphorylation of glucose to glucose 6-phosphate is catalyzed by glucokinase (figure 4.2) in the liver.
In skeletal muscle, and most other peripheral tissues, glucose is phosphorylated by hexokinase.
Glucokinase and hexokinase perform the same reaction but have very different enzyme kinetics. Glucokinase (in the liver) has a higher \(K_m\) (lower affinity for glucose) when compared to hexokinase. In the liver, this enzyme will phosphorylate glucose only when glucose concentrations are high such as in the fed state. Glucokinase also has a high \(V_{max}\) and is therefore not rapidly saturated. This allows for continuous glucose uptake when glucose levels are high allowing for glucose storage and the rapid removal of glucose from circulation, minimizing the likelihood of hyperglycemia. In contrast, hexokinase has a lower \(K_m\) and a high affinity for glucose (figure 4.3). This enzyme becomes rapidly saturated over a very small range of glucose concentrations.
Figure 4.3: Comparison of glucokinase and hexokinase kinetics.
Regulation of glucokinase and hexokinase
Hexokinase is regulated through feedback inhibition where glucose 6-phosphate will compete with glucose for substrate binding. On the other hand, glucokinase is regulated through an alternative mechanism involving the glucokinase regulatory binding protein (GKRP). This protein will bind glucokinase and trap it in the nucleus. When glucose is high, glucokinase is released into the cytosol to phosphorylate glucose. As fructose 6-phosphate levels increase, this will inhibit the glucokinase reaction by enhancing the rebinding of glucokinase to GKRP, trapping it in the nucleus (figure 4.4).
Phosphofructokinase 1 (PFK1): Fructose 6-phosphate to fructose 1,6-bisphosphate (figure 4.5)
Following glucose phosphorylation to glucose 6-phosphate, the glucose 6-phosphate can be used for glycogen synthesis or the pentose phosphate pathway. Substrate that continues through glycolysis is isomerized to fructose 6-phosphate, which is the substrate for the reaction catalyzed by phosphofructokinase 1 (PFK1).
Regulation of phosphofructokinase 1 (PFK1)
Regulation of phosphofructokinase 1 is primarily through allosteric activation by AMP and fructose 2,6-bisphosphate. High AMP levels would indicate a lack of energy within the cell, and this would increase flux through glycolysis by enhancing the activity of PFK1. PFK1 is also inhibited by citrate and ATP; levels of these compounds are indicative of a high energy state, suggesting there are sufficient oxidation productions and glucose is diverted to storage pathways.
Fructose 2,6-bisphosphate is an important regulator of glycolysis, formed by a shunt in the glycolytic pathway. When there is an excess of fructose 6-phosphate in the cell, this substrate is accepted by phosphofructokinase 2 (PFK2) and converted to fructose 2,6-bisphosphate. This compound, fructose 2,6-bisphosphate, functions as an allosteric activator of PFK1. Additionally, PFK2 can be regulated by covalent modification such as phosphorylation. PFK2 is a bifunctional enzyme and only functions as a kinase when insulin is high and it is dephosphorylated. Under fasted conditions, when glucagon is high, this leads to the phosphorylation and inactivation of PFK2;when the enzyme is phosphorylated, it functions as a phosphatase and is referred to as fructose 2,6-bisphosphatase (FBP2) (figure 4.5).
Pyruvate kinase: Phosphoenol pyruvate to pyruvate
Following the synthesis of fructose 1,6-phosphate, aldolase will cleave this substrate into dihydroxyacetone and glyceraldehyde 3-phosphate. These threecarbon compounds will be used to synthesize pyruvate in the final regulatory step of the pathway catalyzed by pyruvate kinase (PK).
Regulation of pyruvate kinase (PK)
The final regulatory step of glycolysis is the reaction catalyzed by pyruvate kinase. The enzyme converts phosphoenol pyruvate (PEP) to pyruvate. PK can be regulated by phosphorylation and allosteric means. PK is subject to feed-forward activation by fructose 1,6-bisphosphate, which allosterically activates the enzyme, increasing flux in the downward direction. As energy levels in the cell increase, ATP levels will reduce enzyme activity through allosteric inhibition (figure 4.6). PK can also be regulated through phosphorylation. Similar to PFK2, PK is dephosphorylated and active in the fed state but phosphorylated during the fasted state, which renders the enzyme inactive; the phosphorylation is glucagon mediated.
Movement of NADH from the cytosol to the mitochondria
The NADH generated in the cytosol by glycolysis must be oxidized back to NAD+ in order to maintain a pool of NAD+ needed for glucose oxidation. As NADH oxidation takes place in the mitochondria, and the membrane is not permeable to NADH, two shuttles are used to move cytosolic NADH into the mitochondria. These processes are a way to get energy out of cytoplasmic NADH into the mitochondria.
Glycerol 3-phosphate shuttle
The glycerol 3-phosphate shuttle is the major shuttle used in most tissues to move NADH from the cytosol to the mitochondria for oxidation. In this pathway, NAD+ is regenerated by glycerol 3-phosphate dehydrogenase, which transfers electrons from NADH to dihydroxyacetonephosphate to generate glycerol 3-phosphate. Glycerol 3-phosphate can diffuse across the mitochondrial membrane where it will donate electrons to membrane bound FAD (bound to succinate dehydrogenase) (figure 4.7).
Malate-aspartate shuttle
Many tissues also contain the malate-aspartate shuttle, which can also carry cytosolic NADH into the mitochondria. Cytosolic NADH is used to reduce oxaloacetate (OAA) to malate, which can cross the mitochondrial membrane. Once inside the mitochondria, malate can be oxidized to OAA to produce NADH. OAA canʼt pass through the mitochondrial membrane, so it requires transamination to aspartate, which can be shuttled into the cytosol to regenerate the cycle (figure 4.8).
Pyruvate dehydrogenase complex
Under aerobic conditions, the pyruvate produced by glycolysis will be oxidized to acetyl-CoA using the pyruvate dehydrogenase complex (PDC). This enzyme is a key transition point between cytosolic and mitochondrial metabolism. This complex is composed of threesubunits, which require the cofactorsthiamine pyrophosphate, lipoic acid, and FADH\(_2\); NADH is also required for the reaction to move forward. The enzyme is highly regulated by both covalent and allosteric regulation. Deficiencies of the PDC can be recessive or X-linked (depending on the subunit deficient) and present with symptoms of lactic acidosis after consuming a meal high in carbohydrates. This metabolic deficiency can be managed by delivering a ketogenic diet and bypassing glycolysis all together.
Regulation of the pyruvate dehydrogenase complex (PDC)
The PDC is regulated by allosteric and covalent regulations. The complex itself can be allosterically activated by pyruvate and NAD+. Elevation of substrate (pyruvate) will enhance flux through this enzyme as will the indication of low energy states as triggered by high NAD+ levels. The PDC is also inhibited by acetyl-CoA and NADH directly. Product inhibition is a very common regulatory mechanism,and high NADH would signal sufficient energy levels, therefore decreasing activity of the PDC.
The PDC is also regulated through covalent modification. Phosphorylation of the complex will decrease activity of the enzyme.
The enzyme responsible for phosphorylation of the PDC is pyruvate dehydrogenase kinase. The kinase is regulated inversely to the PDC (figure 4.9). The kinase is most active when acetyl-CoA and NADH are high. These compounds will stimulate the kinase to phosphorylate and inactivate the PDC. The PDC can be dephosphorylated by a calcium-mediated phosphatase.
Summary of pathway regulation
| Metabolic pathway | Major regulatory enzyme(s) | Allosteric effectors | Hormonal effects |
| Glycolysis (pyruvate oxidation) | Glucokinase (liver) | GKRP | |
| Hexokinase | Glucose 6P (-) | ||
| PFK-1 | Fructose 2,6-BP, AMP (+) Citrate (-) | Insulin/Glucagon ratio >1 → dephosphorylation of PFK2 and increased production of F 2,6-BP | |
| Pyruvate kinase | Fructose 1,6-BP (+) ATP, alanine (-) | Insulin/Glucagon ratio >1 → dephosphorylation | |
| Pyruvate dehydrogenase complex | PDC | Pyruvate, NAD+ (+) Acetyl-CoA, NADH, ATP (-) | Insulin/Glucagon ratio >1 → dephosphorylation |
Table 4.1: Summary of pathway regulation.
References and resources
Text
Ferrier, D. R., ed. Lippincott Illustrated Reviews: Biochemistry, 7th ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins, 2017, Chapter 6: Bioenergetics and Oxidative Phosphorylation: Section V, VI, Chapter 8: Introduction to Metabolism and Glycolysis, Chapter 9: TCA Cycle and Pyruvate Dehydrogenase Complex: Section IIA, IIB, Chapter 11: Glycogen Metabolism: Section V, VI, Chapter 16: Fatty Acid Ketone Body and TAG Metabolism: Section II, IV, V, Chapter 23: Metabolic Effect of Insulin and Glucagon, Chapter 25: Diabetes Mellitus.
Le, T., and V. Bhushan. First Aid for the USMLE Step 1, 29th ed. New York: McGraw Hill Education, 2018, 72–78, 85–89.
Lieberman, M., and A. Peet, eds. Marks' Basic Medical Biochemistry: A Clinical Approach, 5th ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins, 2018, Chapter 2: The Fed or Absorptive State, Chapter 19: Basic Concepts of Regulation: Section IV.A.1.2, Chapter 20: Cellular Bioenergetics, Chapter 22: Generation of ATP from Glucose: Section I.A.B.C, III, Chapter 24: Oxidative Phosphorylation and the ETC: Section I.E, II, III, Chapter 31: Synthesis of Fatty Acids: Section I.A.B, IV, V.
Figures
Grey, Kindred, Figure 4.1 Summary of glycolysis... 2021. https://archive.org/details/4.1_20210924. CC BY 4.0.
Grey, Kindred, Figure 4.2 Regulatory step committed by hexo or glucokinase... 2021. https://archive.org/details/4.2_20210924. CC BY 4.0.
Grey, Kindred, Figure 4.4 Regulation of glucokinase by glucokinase regulatory protein. 2021. https://archive.org/details/4.4_20210924. CC BY 4.0. Added ion channel by Léa Lortal from Noun Project and sphere by Pablo Rozenberg from Noun Project.
Grey, Kindred, Figure 4.5 Regulation of PFK1 by fructose 2,6-bisphosphate generated by PFK2. 2021. https://archive.org/details/4.5-new. CC BY 4.0.
Grey, Kindred, Figure 4.6 Regulation of pyruvate kinase phosphorylation and fructose 1,6-bisphosphate. 2021. https://archive.org/details/4.6-new. CC BY 4.0.
Grey, Kindred, Figure 4.7 Glycerol 3-phosphate shuttle. 2021. https://archive.org/details/4.7_20210924. CC BY 4.0. Added ion channel by Léa Lortal from the Noun Project.
Grey, Kindred, Figure 4.8 Malate-aspartate shuttle. 2021. https://archive.org/details/4.8_20210924. CC BY 4.0.
Lieberman M, Peet A. Figure 4.3 Comparison of glucokinase and hexokinase kinetics. Adapted under Fair Use from Marks' Basic Medical Biochemistry. 5th Ed. pp 154. Figure 9.4 A comparison between hexokinase I and glucokinase. 2017.
Lieberman M, Peet A. Figure 4.9 Regulation of the PDC. Adapted under Fair Use from Marks' Basic Medical Biochemistry. 5th Ed. pp 471. Figure 23.15 Regulation of pyruvate dehydroenase complex (PDC). 2017.
FAQs
Which answer is true about pyruvate dehydrogenase complex? ›
Which of the following is true about the pyruvate dehydrogenase complex? It catalyzes oxidative decarboxylation.
What does PDC do in glycolysis? ›The pyruvate dehydrogenase complex (PDC) is an important gatekeeper enzyme connecting glycolysis to the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS). Thereby, it has a strong impact on the glycolytic flux as well as the metabolic phenotype of a cell.
What is the pyruvate dehydrogenase complex a link between glycolysis and? ›The pyruvate dehydrogenase complex (PDC) controls pyruvate entry into the tricarboxylic acid cycle and thus sits at the interface between glycolysis and glucose oxidation.
What is the outcome of the pyruvate dehydrogenase PDH complex? ›The pyruvate dehydrogenase complex (PDC)3 catalyzes the oxidative decarboxylation of pyruvate with the formation of acetyl-CoA, CO2 and NADH (H+) (1,–3).
What does the pyruvate dehydrogenase complex do quizlet? ›What is the role of the PDH complex? To catalyze the oxidation of Pyruvate to Acetyl CoA thereby providing a link between glycolysis and TCA cycle.
What is the pyruvate dehydrogenase complex and why is it important? ›The Pyruvate Dehydrogenase Complex (PDHc), a mitochondrial matrix multienzyme complex, plays an important role in energy homeostasis in the heart by providing the link between glycolysis and the tricarboxylic acid (TCA) cycle. In TCA cycle, PDHc catalyzes the conversion of pyruvate into acetyl-CoA.
What does the PDC produce? ›The mammalian pyruvate dehydrogenase complex (PDC) is a mitochondrial multienzyme complex that connects glycolysis to the tricarboxylic acid cycle by catalyzing pyruvate oxidation to produce acetyl-CoA, NADH, and CO2.
How many ATP does PDC produce? ›Glycolysis can be divided into two parts, the preparative phase, which requires two ATP, and the energy producing phase, which produces NADH and ATP. The net result of glucose oxidation through glycolysis is two ATP, two NADH and two pyruvate.
What does PDC do in a reaction? ›Since PDC is less acidic than PCC it is often used to oxidize alcohols that may be sensitive to acids. In methylene chloride solution, PDC oxidizes 1º- and 2º-alcohols in roughly the same fashion as PCC, but much more slowly. However, in DMF solution saturated 1º-alcohols are oxidized to carboxylic acids.
What is pyruvate dehydrogenase quizlet? ›What is the function of the pyruvate dehydrogenase complex? The PDH oxidizes pyruvate into acetyl CoA and CO₂. This reaction generates NADH.
How is the pyruvate dehydrogenase complex which connects glycolysis to respiration regulated quizlet? ›
-The pyruvate dehydrogenase complex is regulated to respond to the energy charge of the cell. (A) The complex is inhibited by its immediate products, NADH and acetyl CoA, as well as by the ultimate product of cellular respiration, ATP.
How is the pyruvate dehydrogenase complex regulated quizlet? ›How is Pyruvate dehydrogenase complex regulated? 1. cAMP-dependent protein kinase phosphorylates pyruvate dehydrogenase and shuts it down (inactive). This kinase is activated by ATP, Aceytl CoA and NADH .
What activates the pyruvate dehydrogenase complex? ›The pyruvate dehydrogenase complex is regulated by covalent modification of the first enzyme, pyruvate dehydrogenase (PDH). Pyruvate dehydrogenase kinase inactivates PDH by phosphorylation with ATP (Fig. 6-5). Reactivation is achieved by the action of pyruvate dehydrogenase phosphatase.
What is the pyruvate dehydrogenase PDH reaction? ›The pyruvate dehydrogenase complex catalyzes, through five sequential reactions, the oxidative decarboxylation of pyruvate, an α-keto acid, to form a carbon dioxide molecules (CO2) and the acetyl group of acetyl-coenzyme A or acetyl-CoA, with the release of two electrons, carried by NAD.
What stimulates the pyruvate dehydrogenase complex? ›PDH kinase is stimulated by NADH and acetyl-CoA. It is inhibited by pyruvate. PDH phosphatase is stimulated by Ca++ and insulin. Glycolysis is regulated at the steps catalyzed by hexokinase, PFK-1, and pyruvate kinase.
What happens in the pyruvate dehydrogenase reaction? ›Pyruvate dehydrogenase (PDH) is a convergence point in the regulation of the metabolic finetuning between glucose and FA oxidation. Hence, PDH converts pyruvate to acetyl-coA, and thereby increases the influx of acetyl-coA from glycolysis into the TCA cycle.
What are the 3 functions of pyruvate dehydrogenase? ›Pyruvate Dehydrogenase complex (PDH) connects the citric acid cycle and subsquent oxidative phosphorylation to the glycolysis, gluconeogenesis and lipid and amino acid metabolism pathways.
What type of enzyme is pyruvate dehydrogenase complex? ›Pyruvate dehydrogenase complex is a multifunctional enzyme complex which catalyzes oxidative decarboxylation of pyruvate to acetyl-CoA, NADH, and CO2.
What is pyruvate dehydrogenase complex PDC deficiency? ›Pyruvate dehydrogenase complex (PDC) deficiency is a genetic mitochondrial disorder commonly associated with lactic acidosis, progressive neurological and neuromuscular degeneration and, usually, death during childhood.
What are the 3 enzymes of pyruvate dehydrogenase complex? ›The pyruvate dehydrogenase complex (PDHc) links glycolysis to the citric acid cycle by converting pyruvate into acetyl-coenzyme A. PDHc encompasses three enzymatically active subunits, namely pyruvate dehydrogenase, dihydrolipoyl transacetylase, and dihydrolipoyl dehydrogenase.
What to know about pyruvate dehydrogenase complex MCAT? ›
The pyruvate dehydrogenase complex is a complex of enzymes that decarboxylates and oxidizes pyruvate to form acetyl-CoA and carbon dioxide. The pyruvate from glycolysis is first transported from the cytosol to the mitochondrial matrix, where the pyruvate dehydrogenase complex is located.
Does PDC produce ATP? ›PDC has a special job in the process of producing ATP. The conversion of pyruvate (product of glycolysis) to acetyl CoA (one of the starting products of the citric acid cycle), is accomplished by this very complex (10).
What is PDC activation? ›Plasmacytoid dendritic cells (pDC) are activated indirectly or directly by immune complexes and secrete high amounts of type I interferon in a TLR7 and/or 9-dependent mechanism. From: Systemic Lupus Erythematosus (Second Edition), 2021.
Where is pyruvate dehydrogenase used? ›Pyruvate dehydrogenases (PDHs) represent a cornerstone in cellular energy metabolism, linking glycolysis and the metabolism of branched chain amino acids to the citric acid cycle and lipogenesis.
How many ATP are produced per glycolysis? ›During glycolysis, glucose ultimately breaks down into pyruvate and energy; a total of 2 ATP is derived in the process (Glucose + 2 NAD+ + 2 ADP + 2 Pi --> 2 Pyruvate + 2 NADH + 2 H+ + 2 ATP + 2 H2O).
How many ATP are in one pyruvate? ›As a result, we can say that one molecule of pyruvate produces 15 ATPs in total.
How much ATP is produced in each process? ›How much ATP is produced in all three stages combined? Glycolysis produces 2 ATP molecules, and the Krebs cycle produces 2 more. Electron transport from the molecules of NADH and FADH2 made from glycolysis, the transformation of pyruvate, and the Krebs cycle creates as many as 32 more ATP molecules.
What is the end result of the PDC reaction? ›What is the end result of the PDC reaction? Acetyl CoA containing a high energy thioester bond to be fed into the citric acid cycle.
What does PDC Energy stand for? ›Petroleum Development Corporation Now PDC Energy - PDC Energy, Inc.
What is PDC control? ›PDC, or Park Distance Control, is a parking assistant that can help you park easily and safely.
What is true about pyruvate dehydrogenase? ›
Pyruvate dehydrogenase (PDH) is a convergence point in the regulation of the metabolic finetuning between glucose and FA oxidation. Hence, PDH converts pyruvate to acetyl-coA, and thereby increases the influx of acetyl-coA from glycolysis into the TCA cycle.
What is the pyruvate dehydrogenase complex _____? ›Pyruvate dehydrogenase complex (PDC) is a complex of three enzymes that converts pyruvate into acetyl-CoA by a process called pyruvate decarboxylation.
What does pyruvate dehydrogenase complex contain? ›PDHC contains three enzymes: pyruvate dehydrogenase, dihydrolipoyl transacetylase, and dihydrolipoyl dehydrogenase. The three enzymes collectively work to convert pyruvate into acetyl-CoA, NADH, and CO2 via oxidative carboxylation.
Where does pyruvate dehydrogenase work? ›The PDH complex is a nuclear-encoded multienzymatic assembly present in the mitochondria of most living organisms and is especially prominent in all energy-demanding tissues.
What activates pyruvate dehydrogenase? ›Pyruvate dehydrogenase kinase is activated by ATP, NADH and acetyl-CoA. It is inhibited by ADP, NAD+, CoA-SH and pyruvate. Each isozyme responds to each of these factors slightly differently. NADH stimulates PDK1 activity by 20% and PDK2 activity by 30%.