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23.1 Alt: Overview of Metabolism - Biology

23.1 Alt:  Overview of Metabolism - Biology


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An Overview of Metabolic Pathways - Catabolism

Biological cells have a daunting task. They must carry out 1000s of different chemical reactions required to carry out cell function. These reactions can include opposing goals such as energy production and energy storage, macromolecule degradation and synthesis, and breakdown and synthesis of small molecules. All of these reactions are catalyzed by proteins and RNAs enzymes whose activities must be regulated, again through chemical reactions, to avoid a futile and energy wasting scenario of having opposing pathways functioning simultaneously in a cell.

Metabolism can be divided into two main parts, catabolism, the degradation of molecules, usually to produce energy or small molecules useful for cell function, and anabolism, the synthesis of larger biomolecules from small precursors.

CATBOLISM: Catabolic reactions involve the breakdown of carbohydrates, lipids, proteins, and nucleic acids to produce smaller molecules and biological energy in the form of heat or small thermodynamically reactive molecules like ATP whose further degradation can drive endergonic process such as biosynthesis. Our whole world is reliant on the oxidation of organic hydrocarbons to water and carbon dioxide to produce energy (at the expense of releasing a potent greenhouse gas, CO2). In the biological world, reduced molecules like fatty acids and partially oxidized molecules such as glucose polymers (glycogen, starch), as well as simple sugars, can be partially or fully oxidized to ultimately produce CO2 as well. Energy released from oxidative reactions is used to produce molecules like ATP as well as heat. Oxidative pathways include glycolysis, the tricarboxylic acid cycle (aka Kreb's cycle) and mitochondrial oxidative phosphorylation/electron transport. To fully oxidize carbon in glucose and fatty acids to carbon dioxide requires splitting C-C bonds and the availability of series of oxidizing agents that can perform controlled, step-wise oxidation reactions, analogous to the sequential oxidation of methane, CH4 to methanol (CH3OH), formaldehyde (CH2O) and carbon dixoxide.

  • Glycolysis: This most primitive of metabolic pathways is found in perhaps all organisms. In glycolysis, glucose (C6H12O6), a 6C molecule, is split (or lysed) into two, 3C carbon molecules, glyceraldehyde-3-phosphate, which are then partially oxidized under anaerobic conditions (without O2) to form two molecules of pyruvate (CH3COCO2-). Instead of the very strong oxidizing agent, O2, a weaker one, NAD+ is used, which is reduced in the process to form NADH. Since none of the carbon atoms is oxidized to the state of CO2, little energy is released compared to the complete oxidation to CO2. This pathway comes to a screeching halt if all cellular NAD+ is converted to NADH as NAD+ is not replenished by the simple act of breathing as is the case with O2 in aerobic oxidation. To prevent the depletion of NAD+ from inhibiting the cycle and to allow the cycle to continue under anaerobic conditions, excess NADH is reconverted to NAD+ when the other product of glycolysis, pyruvate is converted to lactate by the enzyme lactate dehydrogenase. Glycolysis occurs in the cytoplasm of the cell.

Figure: Summary of Glycolysis

  • Tricarboxylic Acid (Kreb's) Cycle: The TCA cycle is an aerobic pathway which takes place in an intracellular organelle called the mitochondria. It takes pyruvate, the incompletely oxidized product from glycolysis, and finishes the job of oxidizing the 3C atoms all the way to CO2. First the pyruvate moves into the mitochondria where is is oxidized to the 2C molecule acetylCoA with the release of one CO2 by the enzyme pyruvate dehydrogenase. The acetyl-CoA then enters the TCA cycle where two more CO2 are released. As in glycolysis, C-C bonds are cleaved and C is oxidized by NAD+ and another related oxidizing agent, FAD. What is very different about this pathway is that instead of being a series of linear, sequential reactions with one reactant (glucose) and one product (two pryuvates), it is a cyclic pathway. This has significant consequences since if any of the reactants within the pathways becomes depleted, the whole cyclic pathway can slow down and stop. To see how this happens consider the molecule oxaloacetate (OAA) which condenses with acetyl-CoA to form citrate (see diagram below). In this reaction, one OAA is consumed. However, when the cycle returns, one malate is converted to OAA so there is no net loss of OAA, unless OAA is pulled out of the TCA cycle for other reactions, which happens.

Figure: Pyruvate Dehydrogenase (mitochondrial) and the TCA Cycle

  • Mitochondrial Oxidative Phosphorylation/Electron Transport: The TCA cycle accomplishes what glycolysis didn't, that is the cleavage of all C-C bonds in glucose (in the form of pyruvate and acetyl-CoA, and the complete oxidation of all C atoms to CO2. Yet two problem remains. The pool of oxidizing molecules, NAD+ and FAD get converted to their reduced forms, NADH and FADH2. Unless NAD+ and FAD are regenerated, as was the case in anaerobic conditions when pyruvate gets converted to lacate, the pathway would again come to a grinding halt. In addition, not much ATP is made in the cycle (in the form of a related molecule GTP). Both these problems are resolved as the resulting NADH and FADH2 formed are reoxidized by mitochondrial membrane enzyme complexes which pass electrons from the oxidized NADH and FADH2 to increasingly potent oxidizing agents until they are accepted by the powerful oxidant O2,which is converted reduced to water. The net oxidation of NADH and FADH2 by dioxygen is greatly exergonic, and the energy released by the process drives the synthesis of ATP from ADP and Pi by an mitochondrial enzyme complex, the F0F1ATPase.

Figure: Mitochondrial Electron Transport/Oxidative Phosphorylation

Feeder Pathways: Other catabolic pathways produce products that can enter glycolysis or the TCA cycle. Two examples are given below.

  • Complex carbohydrates: In mammals, the major carbohydrate storage molecule is glycogen, a polymer of glucose linked a1-4 with a1-6 branches. The terminal acetal linkages in this highly branched polymer is cleaved sequentially at the ends not through hydrolysis but through phosphorolysis to produce lots of glucose-1-phosphate which can enter glycolysis.

  • Lipids: Lipids are stored mostly as triacylglycerides in fat cells (adipocytes). When needed for energy, fatty acids are hydrolyzed from the glycerol backbone of the triacylglyceride, and send into cells where they broken down in an oxidative process to form acetyl-CoA with the concomitant production of lots of NADH and FADH2. These can then enter the mitochondrial oxidative phosphorylation/electrons transport system, which produces, under aerobic conditions, lots of ATP.

  • Proteins: When intracellular proteins get degraded, they from individual amino acids. The amine N is lost as it enters the urea cycle. The rest of some amino acid structures can be ultimately converted to acetyl-CoA or keto acids (like alpha-ketoglutarate- a-KG) that are TCA intermediate. These amino acids are called ketogenic. Alternatively, some amino acids, after deamination, are coveted to pyruvate which can either enter the TCA cycle or in the liver be used to synthesize glucose in an anabolic process. These amino acids are called glucogenic. Chemical reactions such as these can be used to replenish intermediates in the TCA cycle which can become depleted as they are withdraw for other reactions.

Anabolic Reactions

Anabolic reactions are those that lead to the synthesis of biomolecules. In contrast to the catabolic reactions just discussed (glycolysis, TCA cycle and electron transport/oxidative phosphorylation) which lead to the oxidative degradation of carbohydrates and fatty acids and energy release, anabolic reactions lead to the synthesis of more complex biomolecules including biopolymers (glycogen, proteins, nucleic acids) and complex lipids. Many biosynthetic reactions, including those for fatty acid synthesis, are reductive and hence require reducing agents. Reductive biosynthesis and complex polymer formation require energy input, usually in the form of ATP whose exergonic cleavage is coupled to endergonic biosynthesis.

Cells have evolved interesting mechanism so as not to have oxidative degradation reactions (which release energy) proceed at the same time and in the same cell as reductive biosynthesis (which requires energy input). Consider this scenario. You dive into a liver cell and find palmitic acid, a 16C fatty acid. From where did it come? Was it just synthesized by the liver cell or did it just enter the cell from a distant location such as adipocytes (fat cells). Should it be oxidized, which should happen if there is a demand for energy production by the cell, or should the liver cell export it, perhaps to adipocytes, which might happen if there is an excess of energy storage molecules? Cells have devised many ways to distinguish these opposing needs. One is by using a slightly different pool of redox reagents for anabolic and catabolic reactions. Oxidative degradation reactions typically use the redox pair NAD+/NADH (or FAD/FADH2) while reductive biosynthesis often uses phosphorylated variants of NAD+, NADP+/NADPH. In addition, cells often carry out competing reactions in different cellular compartments. Fatty acid oxidation of our example molecule (palmitic acid) occurs in the mitochondrial matrix, while reductive fatty acid synthesis occurs in the cytoplasm of the cell. Fatty acids entering the cell destined for oxidative degradation are transported into the mitochondria by the carnitine transport system. This transport system is inhibited under conditions when fatty acid synthesis is favored. We will discuss the regulation of metabolic pathways in a subsequent section. One of the main methods, as we will see, is to activate or inhibit key enzymes in the pathways under a given set of cellular conditions. The key enzyme in fatty acid synthesis, acetyl-CoA carboxylase, is inhibited when cellular conditions require fatty acid oxidation.

The following examples give short descriptions of anabolic pathways. Compare them to the catabolic pathways from the previous section.

  • Glucose synthesis, better known as Gluconeogenesis: In glycolysis, glucose (C6H12O6), a 6C molecule, is converted to two, 3C molecules (pyruvate) in an oxidative process that requires NAD+ and makes two net ATP molecules. In a few organs, most predominately in the liver, the reverse pathway can take place. The liver does this to provide glucose to the brain when the body is deficient in circulating glucose, for example, under fasting and starving conditions. (The liver under these conditions can get its energy from oxidation of fatty acids). The reactions in gluconeogenesis are the same reactions in glycolysis but run in reverse, with the exception of three glycolytic steps which are essentially irreversible. These three steps have bypass enzymes in the gluconeogenesis pathway. Although the synthesis of glucose is a reductive pathway, it uses NADH instead of NADPH as the redundant as the same enzyme used in glycolysis is simply run in reverse. Gluconeogenesis, which also occurs in the cortex of the kidney, is more than just a simple reversal of glycolysis, however. It can be thought of as the net synthesis of glucose from non-carbohydrate precursors. Pyruvate, as seen in the section on catabolism, can be formed from protein degradation to glucogenic amino acids which can be converted to pyruvate. It can also be formed from triacylglycerides from the 3C molecule glycerol formed and released from adipocytes after hydrolysis of three fatty acids from triacylglycerides. However, in humans, glucose can not be made in net fashion from fatty acids. Fatty acids can be converted to acetyl-CoA by fatty acid oxidation. The resulting acetyl-CoA can not form pyruvate since the enzyme that catalyzes the formation for acetyl-CoA from pyruvate, pyruvate dehydrogenase, is irreversible and there is no bypass reaction known. The acetyl-CoA can enter the TCA cycle but since the pathway is cyclic and proceeds in one direction, it can not form in net fashion oxaloacetate. Although oxaloacetate can be remove from the TCA cycle and be use to form phosphoenolpyuvate, a glycolytic intermediate, one acetyl-CoA condenses with one oxaloacetate to form citrate which leads back to one oxaloacetate. Hence fatty acids can not be converted to glucose and other sugars in a net fashion.

Figure: Gluconeogenesis

  • Pentose Phosphate Shunt: This two-part pathway doesn't appear to start as a reductive biosynthetic pathway as the first part is the oxidative conversion of a glycolytic intermediate, glucose-6-phosphate, to ribulose-5-phosphate. The next, nonoxidative branch leads to the formation of ribose-5-phosphate, a key biosynthetic intermediate in nucleic acid synthesis as well as erthyrose-4-phosphate used for biosynthesis of aromatic amino acids . The oxidative branch is important in reductive biosynthesis as it is a major source of the reductant NADPH used in biosynthetic reactions.

  • Fatty acid and isoprenoid/sterol biosynthesis: Acetyl-CoA is the source of carbon atoms for the synthesis of more complex lipids such as fatty acids, isoprenoids, and sterols. When energy needs in a cell are not high, citrate, the condensation product of oxaloacetate and acetyl-CoA in the TCA cycle, builds up in the mitochondrial matrix. It is then transported by the citrate transporter (an inner mitochondrial membrane protein) to the cytoplasm, where it is cleaved back to oxaloacetate and acetyl-CoA by the cytoplasmic enzyme citrate lyase. The oxaloacetate is returned to the mitochondria by conversion first to malate (reduction reaction using NADH), which can move back into the mitochondria through the malate transporter, or further conversion to pyruate, using the cytosolic malic enzyme, which uses NADP+ to oxidize malate to pyruvate which then enters the mitochondria. The acetyl-CoA formed in the cytoplasm can then be used in reductive biosynthesis using NADPH as the reductant to form fatty acids, isoprenoids, and sterols. The NADPH for the reduction comes from the oxidative branch of the pentose phosphate pathway and from the reaction catalyzed by malic enzyme. The liver cells can still run the glycolytic pathway as the NADH/NAD+ ratio is low in the cytoplasm while NADPH/NADP+ ratio is high.


23.1 Alt: Overview of Metabolism - Biology

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Introduction

Though you may approach a course in anatomy and physiology strictly as a requirement for your field of study, the knowledge you gain in this course will serve you well in many aspects of your life. An understanding of anatomy and physiology is not only fundamental to any career in the health professions, but it can also benefit your own health. Familiarity with the human body can help you make healthful choices and prompt you to take appropriate action when signs of illness arise. Your knowledge in this field will help you understand news about nutrition, medications, medical devices, and procedures and help you understand genetic or infectious diseases. At some point, everyone will have a problem with some aspect of his or her body and your knowledge can help you to be a better parent, spouse, partner, friend, colleague, or caregiver.

This chapter begins with an overview of anatomy and physiology and a preview of the body regions and functions. It then covers the characteristics of life and how the body works to maintain stable conditions. It introduces a set of standard terms for body structures and for planes and positions in the body that will serve as a foundation for more comprehensive information covered later in the text. It ends with examples of medical imaging used to see inside the living body.

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    Kapahi Lab

    Understanding the role of nutrient signaling and metabolism in aging and age-related diseases.

    KAPAHI LAB

    Lab focus

    Dietary restriction (DR), the reduction in nutrient intake without malnutrition, has been well documented as a means to extend lifespan and slow age-related diseases in many systems. We and others have previously demonstrated that lifespan extension by inhibition of the TOR pathway overlaps with the effects of DR in D. melanogaster, S. cerevisiae, and C. elegans. However, other DR response mechanisms exist that remain undiscovered. The overall goal of the Kapahi lab is to understand how an organism responds to nutrient status to influence health and disease.

    We utilize worms, flies, and mice as model systems to understand how nutrients influence age-related changes in specific tissues and disease processes. We take creative approaches to develop models for various human diseases that are influenced by nutrient status using invertebrates. We study how various physiological and molecular processes, including fat metabolism, circadian clocks, advanced glycation end products, calcification, and intestinal permeability, are influenced by nutrients to impact organismal health and survival. We collaborate with multiple groups at University of California, San Francisco, and University of California, Berkeley, to undertake interdisciplinary approaches to translate our findings from multiple models to humans.

    Why it matters

    Our work has relevance to certain age-related human diseases, including diabetes, Alzheimer’s disease, kidney stone formation, intestinal diseases, and obesity. There is an ongoing debate about the limitation of lifespan as a measure of aging and the need to assess healthspan to find the most promising interventions for humans. Through functional measures of different tissue functions and disease models, we are also examining the relationship between healthspan and lifespan.

    Our work on aging in simple animals has led to real possibilities of treating human diseases, something I never thought possible when I began my career.

    LAB DETAILS

    The Kapahi lab is pleased to acknowledge the generous support of the following major funders:

    Dr. Kapahi received his PhD from the University of Manchester, where he worked with Tom Kirkwood. He did his postdoctoral work with Seymour Benzer at Caltech and Michael Karin at University of California, San Diego. He joined the Buck Institute as an assistant professor in 2004.

    Dr. Kapahi has published more than 80 scientific papers and holds three current patents. He has been recognized for his scientific excellence with many awards, including the Eureka Award from the National Institute on Aging, a New Scholar Award from the Ellison Medical Foundation, a Glenn Award for Research in Biological Mechanisms of Aging, the Nathan Shock Young Investigator Award, and the Breakthrough in Gerontology and Julie Martin Mid-career awards from AFAR. He currently serves on the editorial board of Aging Cell, Aging, and PLOS Genetics. Dr. Kapahi also initiated the first master’s degree course in gerontology at the Buck Institute.

    Dr. Bar joined the Kapahi lab as a postdoctoral research fellow in July 2018. He received his Ph.D. in Biological Sciences from Indian Institute of Science Education and Research Kolkata, India where he studied lysosomal storage disorders using Drosophila and cell culture. At Buck, he utilizes Drosophila genetics, molecular biology, and bioinformatics tools to understand the environmental and genetic factors responsible for neurodegeneration in Alzheimer’s and related diseases. He recently received the Larry L. Hillblom postdoctoral fellowship grant (2019).

    Huixun "Zoe" Du joined the Kapahi lab as a graduate student from the University of Southern California-Buck Biology of Aging Ph.D. program in April 2020. Prior to this, she completed her B.S. in pharmaceutical sciences at the University of California-Irvine. She is eager to explore the connection between MGO molecules and chronic systemic inflammation.

    Natalie Hill is originally from Palos Verdes, CA. She recently graduated from Pomona College with a BA in biology and also participated on the water polo team there. Her hobbies include exploring the outdoors (hiking, backpacking, camping), exercising, and listening to music.

    Tyler holds a bachelor's degree in physics from Texas Tech University and a master's degree in biology from the University of Texas at San Antonio. His PhD studies in both the Kapahi and Brem labs focus on using computational and biological tools to understand the relationships between metabolites, genes, and aging-related phenotypes in Drosophila melanogaster.

    Dr. Hodge joined the Kapahi lab as a postdoctoral research fellow in the summer of 2016. He received his PhD in physiology from the University of Kentucky and completed a short postdoc at the University of Florida prior to starting at the Buck. His research is focused on understanding how environmental factors such as nutrients and light influence circadian gene expression and the processes of aging. He utilizes Drosophila genetics and bioinformatic (RNA-Seq, ChIP-Seq) and molecular genetic approaches to identify transcriptional regulators of circadian clocks and longevity. Brian also serves as vice president of the Postdoctoral Association at the Buck.

    Kiyomi joined the Kapahi lab as a postdoctoral research fellow under the co-mentorship of Judith Campisi in 2021. She received her PhD from UC Santa Cruz where her research focused on understanding epigenetic inheritance using the model organism C. elegans. Her research at the Buck Institute, aims to understand the role of advanced glycation end products (AGEs) in cellular senescence and age-related neurodegenerative diseases using in vitro and in vivo mammalian model systems.

    Charles Lau earned his degree in molecular cell biology at Dominican University of California in the Spring of 2019. Charles has a great passion for discovery and aspires to reach great heights in his research and studies. He is currently studying as a graduate student at the Buck Institute, where he is working in the Kapahi lab researching ocular degeneration and how it is link to aging in fruit flies. He hopes to one day further expand his knowledge on stem cells and its benefits for humanity.

    Durai joined the Kapahi lab as a Staff Scientist in 2020. His research is focused on deciphering the role of advanced glycation end products (AGEs) in aging and Alzheimer’s disease (AD). His work will determine the metabolic networks that influence the production of AGEs and determine the mechanisms by which hyperglycemia enhances the risk of AD. Before joining the Buck Institute, he worked as a postdoctoral research associate at the Washington State University. In his previous research, Durai characterized the function of neuronal G-protein coupled receptors (GPCRs) and uncovered the mechanism and role of neurotransmitters in regulating immunity and aging in C. elegans. Durai held fellowships at the University of Hyderabad and Alagappa University in India where he completed his PhD in understanding host-pathogen interactions using C. elegans as a model.

    Muniesh is interested in understanding adult-onset disease mechanisms with a specific focus on neurodegeneration and aging. He did his doctoral research on the regulation of synaptic vesicles’ fast axonal transport in neurons of C. elegans at National Tsing Hua University (Taiwan). He is currently studying the role of Advanced Glycation End-products (AGEs) in accelerating aging and neurodegeneration in C. elegans. Muniesh’s other interests include development of C. elegans models for neurodegenerative diseases, understanding exercise physiology and nutrition.

    Kenneth received his bachelor’s degree in molecular and cell biology from University of California Berkeley, his master’s degree in biological sciences from Dominican University of California and his PhD from University of Southern California. His current research focuses on understanding how natural genetic variation can influence response to diet to affect longevity and health.

    Lauren is a recent Master's graduate from Dominican University. She performed her thesis work through the Kapahi Lab, studying advanced glycation end-products and their role in diabetic complications. Lauren now continues studying methylglyoxal effects on feeding behavior and metabolic disorders in mammalian models as a Research Associate in the Kapahi Lab.

    Research and Publications

    1. Investigating the Role of Advanced Glycation End (AGE) products in aging, diabetes, and neurodegeneration

    Diabetes is a metabolic disease resulting from elevated glucose over a prolonged period. In the United States, 11.3 percent of all adults 20 or over have diabetes. Diabetes overall at least doubles the risk of death. Diabetes leads to various complications and organ failure, including cardiovascular diseases, kidney failure, diabetic retinopathy in the United States in 2010. Diabetes also more than doubles the risk of Alzheimer’s and Parkinson’s disease. However, the mechanisms by which diabetes causes these pathologies remain poorly understood

    Fig. 1. Biochemical model showing points of intervention to decrease the neurodegeneration-inducing effects of MGO and AGEs. The balance between production of MGO from glycolysis and detoxification determines the steady-state level of MGO, which in turn drives the rate of AGE formation. AGEs promote neurodegeneration and aging. Numbers 1–4 represent sites of interventions designed to ameliorate AGE-mediated toxicity.

    Our working hypothesis is that prolonged elevation of glucose leads to glycation of macromolecules like protein and lipids, by forming Advanced Glycation End-products (AGEs). Methylglyoxal (MGO) and other glyoxals, which are unavoidable byproducts of anaerobic glycolysis and lipid peroxidation, react indiscriminately with proteins, lipids, and DNA to yield a heterogeneous array of molecules collectively called AGEs The formation of AGEs damages cellular macromolecules and has been associated with the complications of diabetes and other diseases. We have developed a model to study various pathologies including diabetic neuropathy, neurotoxicity, and accelerated aging using C. elegans within a two-week timeframe. We have established a C. elegans model, based on impaired glyoxalases (GLO1 or DJ-1), to broadly study MGO related stress. We show that, in comparison to wild-type animal, the mutants rapidly exhibit several pathogenic phenotypes, including hyperesthesia, neuronal damage, reduced motility, and early mortality. We further demonstrate TRPA-1/TRPA1 as a sensor for a-DCs, conserved between worms and mammals. Moreover, TRPA-1 activates SKN-1/Nrf via calcium-modulated kinase signaling, ultimately regulating the glutathione-dependent (GLO1) and co-factor-independent (DJ1) glyoxalases to detoxify a-DCs. Using our model, we are uncovering genetic and pharmacological targets that modulate the onset of AGEs pathology in our worm model at different steps shown in Figure 1. We are currently pursuing these targets in various models of neurodegenerative diseases using worms, mice, and induced pluripotent stem cells.

    Dietary Restriction (DR) is the reduction of particular or total nutrient intake without causing malnutrition. DR extends lifespan and delays the onset of age-related neurodegeneration in models of neurodegenerative disease in diverse organisms, including yeast, flies, and rodents. Several studies in mice have documented that caloric restriction or time-restricted feeding slow age-related neurological decline in both normal aging and models of AD. However, the molecular mechanisms through which nutrient restriction protects the brain and other tissues during normal aging and AD are just beginning to be elucidated.

    We propose to use the fly to study this question as it is a well-established and expedient model to study aging, dietary changes, and neurodegenerative diseases. We are also studying the cross-talk between nutrient-sensing pathways and circadian clocks to modulate aging and neurodegeneration. Our interdisciplinary studies involve the use of genetics, proteomics, bioinformatics to define the nutrient responsive pathways that modulate aging and neurodegenration. Furthermore, we are using flies, mice and induced pluripotent stem cells to study pathways that influence aging and neurodegeneration.


    Acknowledgements

    This work was supported by the Claudia Adams Barr Program, the Lavine Family Fund and NIH grant no. DK123095 (E.T.C), NIH grant no. DK123321 (E.L.M.), the National Cancer Center (H.X.), grant no. R01DK078081 (N.N.D.) and the Juvenile Diabetes Research Foundation (A.F.). We thank B. Spiegelman, P. Puigserver, K. Sharabi, E. Rosen, S. Patel and R. Bronson for discussions, the Nikon Imaging Center at Harvard Medical School and the Harvard Center for Biological Imaging for assistance with microscopy, Dana-Farber/Harvard Cancer Center Rodent Histopathology Core (grant no. NIH-5-P30-CA06516) for preparing histology slides and the Harvard Digestive Disease Center, Core D for assistance with bomb calorimetry. Cartoon illustrations in Figs. 1f, 3a, 3h, 4c were created with BioRender.com.


    Metabolism in Plants: Photosynthesis

    Photosynthesis happens in plant cells, some algae and certain bacteria called cyanobacteria. This metabolic process occurs in chloroplasts thanks to chlorophyll, and it produces sugar along with oxygen. The light-dependent reactions, plus the Calvin cycle or light-independent reactions, are the main parts of photosynthesis. It is important for the overall health of the planet because living things rely on the oxygen plants make.

    During the light-dependent reactions in the thylakoid membrane of the chloroplast, chlorophyll pigments absorb light energy. They make ATP, NADPH and water. During the Calvin cycle or light-independent reactions in the stroma, ATP and NADPH help make glyceraldehyde-3-phosphate, or G3P, which eventually becomes glucose.

    Like cellular respiration, photosynthesis depends on redox reactions that involve electron transfers and the electron transport chain.

    There are different types of chlorophyll, and the most common types are chlorophyll a, chlorophyll b and chlorophyll c. Most plants have chlorophyll a, which absorbs blue and red light wavelengths. Some plants and green algae use chlorophyll b. You can find chlorophyll c in dinoflagellates.


    2/ Krebs Cycle (Citric Acid Cycle or Tricarboxylic Acid Cycle)

    In the presence of oxygen, pyruvate enters the Krebs cycle which is the second stage of cellular metabolism. However, before it actually enters this stage, it has to go through a transition stage also known as the preparatory phase.

    Under aerobic conditions, pyruvate molecules are not converted to lactic acid and can therefore enter the mitochondria where they can go through an important transition step.

    Decarboxylation - This transition step is known as decarboxylation and involves the conversion of the pyruvate molecules to Acetyl-CoA by the enzyme pyruvate dehydrogenase.

    As the name suggests, this step involves the removal of carbon (the form of CO2) from the pyruvate by the enzyme pyruvate dehydrogenase.

    The enzyme adds Coenzyme A to the 2 pyruvate molecules in the presence of NAD+ which not only results in the production of 2 Acetyl-CoA but also converts the NAD+ molecules to 2 molecules of NADH.

    The following are the main steps involved in Kreb's cycle:

    Step 1: Citrate synthesis - In the first step of Kreb's cycle, acetyl CoA produced during the transition stage combines with oxaloacetate (OAA) in the presence of the enzyme citrate synthase to form citrate.

    As the name of the enzyme suggests, it's involved in the synthesis of citrate by combining acetyl CoA which is a two (2) carbon molecule and oxaloacetate, a four-carbon molecule.

    * Step 1 of Kreb's cycle is highly regulated. Some of the molecules that regulate the function of the enzyme citrate synthase include ATP, NADH, and citrate. When there is a high amount of citrate (the molecule synthesized by the enzyme), it sends feedback limiting its activities.

    Step 2: Isomerization - The second step is an isomerization reaction and results in the production of isocitrate. Here, the enzyme aconitase transforms the citrate to isocitrate by rearranging carbon molecules.

    Here, it's worth noting that the process is reversible which means the isocitrate can be transformed back to citrate if need be.

    * Isocitrate produced through the isomerization of citrate is less stable compared to citrate.

    Step 3: Decarboxylation - In step 3, isocitrate is converted to alpha-ketoglutarate through a process known as decarboxylation. As the name suggests, this involved the removal of carbon from isocitrate in the form of carbon dioxide.

    In the process, NAD+ is reduced to NADH and a hydrogen ion. This process is catalyzed by the enzyme isocitrate dehydrogenase. In this step, then, NAD+ reacts with isocitrate in the presence of the enzyme which reduces the NAD+ while converting the isocitrate to alpha-ketoglutarate.

    In the presence of too much ATP, the enzyme involved in this reaction is limited thus reducing the production of alpha-ketoglutarate. However, high amounts of ADP promote the action of the enzyme thus enhancing its activities.

    Step 4: Decarboxylation 2 - In step 4, alpha-ketoglutarate is converted to succinyl CoA by the enzyme alpha-ketoglutarate dehydrogenase. In this reaction, NAD+ reacts with alpha-ketoglutarate in the presence of the enzyme alpha-ketoglutarate dehydrogenase which again results in its reduction.

    A carbon is also lost in the form of carbon dioxide resulting in the production of succinyl CoA. In a case where too much energy is produced in the cell, the molecule, succinyl CoA, binds to the enzyme thus limiting its activities. As a result, the production of succinyl CoA is reduced. Some of the other substances that inhibit the enzyme include NADH and calcium.

    Step 5: Hydrolysis - In step 4, a CoA is added resulting in the production of succinyl CoA. In step 5, on the other hand, the CoA is removed resulting in the production of succinate.

    The enzyme involved in this step is known as succinyl CoA synthetase and functions by stimulating the conversion of succinyl CoA to succinate. In this process, CoA is released along with a phosphate.

    Here, a GDP (Guanosine diphosphate) molecule takes up the phosphate to form GTP (Guanosine triphosphate). However, GTP loses the phosphate to ADP which results in the production of ATP. This is known as substrate-level phosphorylation.

    * In step 5, hydrolysis of GTP produced ATP.

    Step 6: Fumarate - In step six (6) of the cycle, succinate is converted to fumarate by the enzyme succinate dehydrogenase. Here, FAD (flavin adenine dinucleotide) reacts with succinate in the presence of the enzyme which results in its reduction to FADH.

    Step 7: Hydrolysis - In step 7, the enzyme fumarase is involved in the hydrolysis of fumarate to form malate.

    Step 8: Production of Oxaloacetate - In this step, the enzyme malate dehydrogenase is involved in the conversion of malate to oxaloacetate. Here, NAD+ reacts with malate in the presence of the enzyme causing it to be reduced to NADH and a hydrogen ion. Once it's produced, Oxaloacetate can then enter the cycle by accepting another molecule of acetyl CoA as the cycle continues.

    * With two molecules of Acetyl CoA, Kreb's cycle produces 4 carbon dioxide molecules, 6 molecules of NADH, 2 molecules of FADH2, as well as 2 ATP molecules. NADH and FADH2 molecules are important for the third and last stage of cellular metabolism.


    CRISPR/Cas Genome Editing and Precision Plant Breeding in Agriculture

    Kunling Chen, Yanpeng Wang, Rui Zhang, Huawei Zhang, Caixia Gao
    Vol. 70, 2019

    Abstract

    Enhanced agricultural production through innovative breeding technology is urgently needed to increase access to nutritious foods worldwide. Recent advances in CRISPR/Cas genome editing enable efficient targeted modification in most crops, thus promising . Read More

    Figure 1: Comparison of breeding methods used in modern agriculture. Cross breeding: improving a trait (e.g., disease resistance) through crossing an elite recipient line with a donor line and selecti.

    Figure 2: CRISPR/Cas systems for genome editing and other manipulations. (a) Two CRISPR/Cas systems used for plant genome engineering: Cas9 and Cpf1. (b) Genome editing with CRISPR/Cas systems can hav.

    Figure 3: Mechanisms of base editing. (a) CBE-mediated C-to-T base-editing strategy. The deaminases include rAPOBEC1, hAID, PmCDA1, and hA3A. (b) ABE-mediated A-to-G base-editing strategy. The deamina.

    Figure 4: Delivery strategies for CRISPR/Cas systems to plants. (a) Traditional delivery methods for CRISPR/Cas DNA combined with herbicide or antibiotic selection. Transgene-free plants can be obtain.

    Figure 5: Overview of potential CRISPR/Cas-based applications for plant breeding. CRISPR/Cas-mediated crop trait improvement mainly focuses on yield, quality, and biotic and abiotic resistance. (a) CR.

    Figure 6: Ideal delivery strategies. (Upper panels) Improvements in existing delivery systems and the regulation of developmental genes to overcome species limitations and to speed tissue culture step.


    23.1 Alt: Overview of Metabolism - Biology

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    CYP24A1 is an enzyme expressed in the mitochondrion of humans and other species. It catalyzes hydroxylation reactions which lead to the degradation of 1,25-dihydroxyvitamin D3, the physiologically active form of vitamin D. Hydroxylation of the side chain produces calcitroic acid and other metabolites which are excreted in bile. [5] [6]

    CYP24A1 was identified in the early 1970s and was first thought to be involved in vitamin D metabolism as the renal 25-hydroxyvitamin D3-24-hydroxylase, modifying calcifediol (25-hydroxyvitamin D) to produce 24,25-dihydroxycholecalciferol (24,25-dihydroxyvitamin D). Subsequent studies using recombinant CYP24A1 showed that it could also catalyze multiple other hydroxylation reactions at the side chain carbons known as C-24 and C-23 in both 25-OH-D3 and the active hormonal form, 1,25-(OH)2D3. It is now considered responsible for the entire five-step, 24-oxidation pathway from 1,25-(OH)2D3 producing calcitroic acid. [6]

    CYP24A1 also is able to catalyse another pathway which starts with 23-hydroxylation of 1,25-(OH)2D3 and culminates in 1,25-(OH)2D3-26,23-lactone. [6]

    The side chains of the ergocalciferol (vitamin D2) derivatives, 25-OH-D2 and 1,25-(OH)2D2, are also hydroxylated by CYP24A1. [6]

    The structure of CYP24A1 is highly conserved between different species although the balance of functions can differ. [6] Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

    This enzyme plays an important role in calcium homeostasis and the vitamin D endocrine system through its regulation of the level of vitamin D3.

    Interactive pathway map Edit

    Click on genes, proteins and metabolites below to link to respective articles. [§ 1]


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