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6: Metabolic Pathways - Biology

6: Metabolic Pathways - Biology


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6: Metabolic Pathways

Chapter Outline

Figure 5.1 A hummingbird needs energy to maintain prolonged periods of flight. The bird obtains its energy from taking in food and transforming the nutrients into energy through a series of biochemical reactions. The flight muscles in birds are extremely efficient in energy production.(credit: modification of work by Cory Zanker)

Introduction

Virtually every task performed by living organisms requires energy. Energy is needed to perform heavy labor and exercise, but humans also use a great deal of energy while thinking, and even during sleep. In fact, the living cells of every organism constantly use energy. Nutrients and other molecules are imported, metabolized (broken down) and possibly synthesized into new molecules, modified if needed, transported around the cell, and may be distributed to the entire organism. For example, the large proteins that make up muscles are actively built from smaller molecules. Complex carbohydrates are broken down into simple sugars that the cell uses for energy. Just as energy is required to both build and demolish a building, energy is required for both the synthesis and breakdown of molecules. Additionally, signaling molecules such as hormones and neurotransmitters are transported between cells. Pathogenic bacteria and viruses are ingested and broken down by cells. Cells must also export waste and toxins to stay healthy, and many cells must swim or move surrounding materials via the beating motion of cellular appendages like cilia and flagella.

The cellular processes listed above require a steady supply of energy. From where, and in what form, does this energy come? How do living cells obtain energy, and how do they use it? This chapter will discuss different forms of energy and the physical laws that govern energy transfer. This chapter will also describe how cells use energy and replenish it, and how chemical reactions in the cell are performed with great efficiency.

You will be able to describe these basic functions of metabolism:

  • define metabolism
  • describe the role of enzymes in metabolism
  • recognize that enzymes are proteins
  • describe the role of ATP in cellular processes
  • understand energy production in a cell from sources like glucose
  • understand ATP production from light in photosynthesis

Metabolic Pathways

The processes of making and breaking down sugar molecules illustrate two types of metabolic pathways. A metabolic pathway is a series of interconnected biochemical reactions that convert a substrate molecule or molecules, step-by-step, through a series of metabolic intermediates, eventually yielding a final product or products. In the case of sugar metabolism, the first metabolic pathway synthesized sugar from smaller molecules, and the other pathway broke sugar down into smaller molecules. These two opposite processes—the first requiring energy and the second producing energy—are referred to as anabolic (building) and catabolic (breaking down) pathways, respectively. Consequently, metabolism is composed of building (anabolism) and degradation (catabolism).

Figure 3: This tree shows the evolution of the various branches of life. The vertical dimension is time. Early life forms, in blue, used anaerobic metabolism to obtain energy from their surroundings.

Evolution of Metabolic Pathways

There is more to the complexity of metabolism than understanding the metabolic pathways alone. Metabolic complexity varies from organism to organism. Photosynthesis is the primary pathway in which photosynthetic organisms like plants (the majority of global synthesis is done by planktonic algae) harvest the sun’s energy and convert it into carbohydrates. The by-product of photosynthesis is oxygen, required by some cells to carry out cellular respiration. During cellular respiration, oxygen aids in the catabolic breakdown of carbon compounds, like carbohydrates. Among the products of this catabolism are CO2 and ATP. In addition, some eukaryotes perform catabolic processes without oxygen (fermentation) that is, they perform or use anaerobic metabolism.

Organisms probably evolved anaerobic metabolism to survive (living organisms came into existence about 3.8 billion years ago, when the atmosphere lacked oxygen). Despite the differences between organisms and the complexity of metabolism, researchers have found that all branches of life share some of the same metabolic pathways, suggesting that all organisms evolved from the same ancient common ancestor ([Figure 3]). Evidence indicates that over time, the pathways diverged, adding specialized enzymes to allow organisms to better adapt to their environment, thus increasing their chance to survive. However, the underlying principle remains that all organisms must harvest energy from their environment and convert it to ATP to carry out cellular functions.


Metabolic profiles of key tissues

Brain

Usually neurons use only glucose as energy source. Since the brain stores only a very small amount of glycogen, it needs a steady supply of glucose. During long fasts, it becomes able to oxidize ketone bodies.

Liver

The maintenance of a fairly steady concentration of glucose in the blood is one of the liver's main functions. This is accomplished through gluconeogenesis and glycogen synthesis and degradation. It synthesizes ketone bodies when acetyl-CoA is plenty. It is also the site of urea synthesis.

Adipose tissue

It synthesizes fatty acids and stores them as triacylglycerols. Glucagon activates a hormone-sensitive lipase, which hydrolizes triacylglycerols yielding glycerol and fatty acids. These are then released into the bloodstream in lipoproteins.

Muscle

Muscles use glucose, fatty acids, ketone bodies and aminoacids as energy source. It also contains a reserve of creatine-phosphate, a compound with a high phosphate-transfer potential that is able to phosphorilate ADP to ATP, thereby producing energy without using glucose. The amount of creatine in the muscle is enough to sustain about 3-4 s of exertion. After this period, the muscle uses glycolysis, first anaerobically (since it is much faster than the citric acid cycle), and later (when the increased acidity slows phosphofrutokinase enough for the citric acid cycle to become non-rate-limiting) in aerobic conditions.

Kidney

It can perform gluconeogenesis and release glucose into the bloodstream. It is also responsible for the excretion of urea, electrolytes, etc. Metabolic acidosis may be increased by the action of the urea cycle, since urea synthesis (which takes place in the liver) uses HCO3 - , thereby further lowering blood pH. Under these circunstances, nitrogen may be eliminated by the joint action of kidney and liver: excess nitrogen is first incorporated in glutamine by glutamine synthetase. Kidney glutaminase then cleaves glutamine in glutamate e NH3, which the kidney immediately excretes. This process allows nitrogen excretion without affecting blood bicarbonate levels.


Glycolysis takes place outside the mitochondria in the cytoplasm. Glycolysis breaks down a molecule of glucose which has six carbon, down into two molecules .

What are the processes involved in cellular respiration? How do enzymes perform an important role in the mitochondria? How does the mitochondria use chemiosm.

Amylase Laboratory Report Introduction: Enzymes are a catalytic protein in a quaternary structure, that helps with the acceleration of molecules called subs.

Substrates are the reactants or starting materials of chemical reactions. The binding of substrate to active sites orients molecules in a way that promote bi.

Enzyme is a catalyst that speed up the chemical reaction of molecules in our body by lowering the activation energy. (Campbell et al., pg. 151 - 152). Activi.

• Sucrose can be broken down into glucose and fructose to produce energy. • Glucose is broken down into a pathway called “glycolysis” which produces pyruvat.

INTRODUCTION Trypsin is a proteolytic enzyme, important for the digestion of proteins. Enzymes are biological catalysts for metabolic process in cells. A cat.

During the first phase called carbon fixation, carbon dioxide (Co2) is fixed from an inorganic molecule to an organic molecule (3-PGA) by the enzyme called R.

Globular proteins have more specific roles and rely on 'pockets ' in their surfaces called binding sites (or active sites in the enzymes case). The shape of.

According to Campbell’s Biology Cellular Respiration is, “[t]he catabolic pathways of aerobic and anaerobic respiration, which break down organic molecules a.


Examples of Catabolism

Carbohydrate and Lipid Catabolism

Almost all organisms use the sugar glucose as a source of energy and carbon chains. Glucose is stored by organisms in larger molecules called polysaccharides. These polysaccharides can be starches, glycogen, or other simple sugars like sucrose. When an animal’s cells need energy, it sends signals to the parts of the body that store glucose, or it consumes food. Glucose is released from the carbohydrates by special enzymes, in the first part of the catabolism. The glucose is then distributed into the body, for other cells to use as energy. The catabolic pathway glycolysis then breaks glucose down even further, releasing energy that is stored in ATP. From glucose, pyruvate molecules are made. Further catabolic pathways create acetate, which is a key metabolic intermediate molecule. Acetate can become a wide variety of molecules, from phospholipids, to pigment molecules, to hormones and vitamins.

Fats, which are large lipid molecules, are also degraded by the metabolism to produce energy and to create other molecules. Similar to carbohydrates, lipids are stored in large molecules, but can be broken down into individual fatty acids. These fatty acids are then converted through beta-oxidation into acetate. Again, acetate can be used by the anabolism, to produce larger molecules, or as part of the citric acid cycle which drives respiration and ATP production. Animals use fats to store large amount of energy for future use. Unlike starches and carbohydrates, lipids are hydrophobic, and exclude water. In this way, a lot of energy can be stored without the heavy weight of water slowing the organism down.

Most catabolic pathway are convergent in that they end in the same molecule. This enables organisms to consume and store energy in a variety of different forms, while still being able produce all the molecules it needs in the anabolic pathways. Other catabolic pathways, such as protein catabolism discussed below, create different intermediate molecules are precursors, known as amino acids, to build new proteins.

Protein Catabolism

If no source of glucose is present, or there are too many amino acids, the molecules will enter further catabolic pathways to be broken down into carbon skeletons. These small molecules can be combined in gluconeogenesis to create new glucose, which the cells can use as energy or store in large molecules. During starvation, cellular proteins can go through the catabolism to allow an organism to survive on its own tissues until more food is found. In this way, organisms can live with only small amounts of water for extremely long times. This makes them much more resilient to changing environmental conditions.


Pyridoxal phosphate (Vitamin B6) metabolism

Pyridoxal 5’-phosphate (PLP) is the active form of vitamin B6, whereas pyridoxamine, pyridoxal and pyridoxine and their phosphate esters form the vitamin B6 complex. PLP is a cofactor crucial for the functioning of many enzymes involved in amino acid metabolism. There are two different routes of de novo PLP synthesis present in different organisms. In the DOXP-dependent first route, the PLP precursor pyridoxine 5’-phosphate (PNP) is produced from 4-phosphohydroxyl-L-threonine (4PHT) and 1-deoxy-D-xylulose-5-phosphate (DOXP) by the actions of the enzymes PdxA and PdxJ. These precursors are synthesised from two independent pathways from metabolites of carbohydrate metabolism. PNP can then be converted to PLP by the enzyme pyridoxal 5’-phosphate synthase (pyridoxamine/pyridoxine 5’-phosphate oxidase). In the DOXP-independent second route, PLP synthesis is catalysed by the actions of Pdx1 and Pdx2 with glutamine, ribulose 5-phosphate (or ribose 5-phosphate) and glyceraldehyde 3-phosphate (or glycerone phosphate) as substrates [1]. The pyridoxine, pyridoxamine and pyridoxal can be phosphorylated with the action of the enzyme pyridoxal kinase (PdxK) and the former two can be converted to the later by the action of pyridoxal 5’-phosphate synthase mentioned above.

Of the two routes mentioned above, DOXP-independent route is responsible for the de novo PLP biosynthesis in apicomplexans Plasmodium falciparum and Toxoplasma gondii. The biosynthesis of PLP was detected in P. falciparum with labelling experiments by Cassera et al [2] and it is then confirmed to be DOXP-independent pathway by Wrenger et al [3]. The de novo biosynthesis of PLP via the action of Pdx1 and Pdx2 enzymes was also experimentally demonstrated in T. gondii [4]. P. falciparum genome also possesses the PdxK enzyme which catalyses phosphorylation of salvaged pyridoxal and other vitamers and its activity has also been experimentally verified [3]. The ortholog of this enzyme is also present in T. gondii genome.


The origins of metabolic disease

In 1908 British physician Sir Archibald Garrod postulated that four inherited conditions of lifelong duration— alkaptonuria, pentosuria, albinism, and cystinuria—were caused by defects in specific biochemical pathways due to the diminished activity or complete lack of a given enzyme. He called these disorders “ inborn errors of metabolism.” Although Garrod was incorrect in his categorization of cystinuria, his insights provided the field of biochemical genetics with a solid foundation, and the list of inherited inborn errors of metabolism has rapidly grown. This article is primarily concerned with these inherited metabolic diseases, although other disorders, including endocrine diseases (e.g., diabetes mellitus and hypothyroidism) and malnutrition (e.g., marasmus and kwashiorkor), also affect cellular metabolism.

Food is broken down in a series of steps by cellular enzymes (proteins that catalyze the conversion of compounds called substrates) into products with a different biochemical structure. These products then become the substrate for the next enzyme in a metabolic pathway. If an enzyme is missing or has diminished activity, the pathway becomes blocked, and the formation of the final product is deficient, resulting in disease. Low activity of an enzyme may result in the subsequent accumulation of the enzyme’s substrate, which may be toxic at high levels. In addition, minor metabolic pathways that usually lie dormant may be activated when a substrate accumulates, possibly forming atypical, potentially toxic, products. Each cell in the body contains thousands of metabolic pathways, all of which are interlinked to some extent, so that a single blockage may affect numerous biochemical processes.


Author Summary

Cancer proliferating cells adapt their metabolism to support the conversion of available nutrients into biomass, which often involves an increased rate of specific metabolic pathways, such as glycolysis. Surprisingly, however, we observe that aggregating individual gene expression using canonical human metabolic pathways frequently fails to enhance the classification of noncancerous vs. cancerous tissues and in the task of predicting cancer patient survival. This supports the notion that metabolic alterations in cancer rewire cellular metabolism through unconventional pathways. Here we introduce a novel algorithm (MCF) that aims to identify these cancer-mediated ‘composite’ metabolic pathways by identifying those that best differentiate between cancerous vs. non-cancerous tissues gene expression. Remarkably, MCF successfully builds robust classifiers integrating different datasets of the same cancer type. We further show that the data-driven pathways identified by MCF, in contrast to the canonical literature-based pathways, successfully generate clinically relevant features that are predictive of breast cancer patients’ survival in an independent dataset. Our findings thus suggest that cancer metabolism may be rewired via non-standard composite pathways.

Citation: Auslander N, Wagner A, Oberhardt M, Ruppin E (2016) Data-Driven Metabolic Pathway Compositions Enhance Cancer Survival Prediction. PLoS Comput Biol 12(9): e1005125. https://doi.org/10.1371/journal.pcbi.1005125

Editor: Teresa M. Przytycka, National Center for Biotechnology Information (NCBI), UNITED STATES

Received: April 22, 2016 Accepted: August 30, 2016 Published: September 27, 2016

Copyright: © 2016 Auslander et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This work was supported by the University of Maryland Institute for Advanced Computer Studies and by a grant from the Israeli Science Foundation (ISF). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of this manuscript.

Competing interests: The authors have declared that no competing interests exist.


Metabolic Engineering of Bacteria

Yield and productivity are critical for the economics and viability of a bioprocess. In metabolic engineering the main objective is the increase of a target metabolite production through genetic engineering. Metabolic engineering is the practice of optimizing genetic and regulatory processes within cells to increase the production of a certain substance. In the last years, the development of recombinant DNA technology and other related technologies has provided new tools for approaching yields improvement by means of genetic manipulation of biosynthetic pathway. Industrial microorganisms like Escherichia coli, Actinomycetes, etc. have been developed as biocatalysts to provide new or to optimize existing processes for the biotechnological production of chemicals from renewable plant biomass. The factors like oxygenation, temperature and pH have been traditionally controlled and optimized in industrial fermentation in order to enhance metabolite production. Metabolic engineering of bacteria shows a great scope in industrial application as well as such technique may also have good potential to solve certain metabolic disease and environmental problems in near future.

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