Name: atcase feedback inhibition in pyrimidine synthesis
Uploaded: 2023-04-30T10:13:14.000Z
Duration: 1 min 19 s
Channel: JoVE

K12 Standards

Tennessee Academic Standards

High School

Biology

from-molecules-to-organisms-structures-and-processes

From Molecules to Organisms: Structures and Processes

BIO1.LS1.3

Allosteric Proteins-ATCase

Proteins that contain linked binding sites are called allosteric proteins and can be of various types, such as enzymes, receptors, structural proteins, and motor proteins.&#160;
For example,&#160; aspartate transcarbamoylase, also known as ATCase, is a large enzyme containing six catalytic subunits, each with a substrate binding site. It also has six additional regulatory subunits, each with a site that can bind both pyrimidines and purines, the building blocks of DNA and RNA.
The enzyme catalyzes an essential step in pyrimidine synthesis, the condensation of aspartate and carbamoyl phosphate to produce carbamoyl aspartate. The rate of this reaction increases in a concentration-dependent manner.
Binding of ATP, a purine, to the enzyme activates the enzyme. Whereas, the simultaneous binding of UTP and CTP, pyrimidines, results in a 95% inhibition of enzyme activity.&#160; &#160;
This regulatory mechanism is essential to maintain the right amount of pyrimidines relative to purines in the cell.&#160;

allosteric proteins-atcase

Binding sites linkages can regulate a protein&#39;s function.&#160; For example, enzyme activity is often regulated through a feedback mechanism where the end product of the biochemical process serves as an inhibitor.
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to&#160; N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis pathway, inhibit the activity of ATCase, the enzyme that catalyzes the first essential step of this pathway. Binding of UTP and CTP to the enzyme negatively regulates the linked catalytic site when the concentration of pyrimidines is high, relative to the concentration of purines in the cell. This phenomenon is known as feedback inhibition and is essential in maintaining the right amounts of metabolites in an organism.
ATCase is part of the CAD multi-enzyme complex, part of the pyrimidine biosynthesis pathway, along with carbamoyl phosphate synthetase II and dihydroorotase. Pyrimidines are essential for DNA synthesis during cell division, therefore, inhibition of ATCase activity slowing down tumor growth in cancer.

Binding sites linkages can regulate a protein&#39;s function.&#160; For example, enzyme activity is often regulated through a feedback mechanism where the ...

Education

JoVE Core

Molecular Biology

Unit 1

Protein Function

KEY TERMS AND CONCEPTS

atcase feedback inhibition in pyrimidine synthesis

ATCase is a key enzyme in pyrimidine synthesis. It is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to form N-carbamoyl-L-aspartate. This reaction starts the pathway that makes pyrimidines.

ATCase is regulated by feedback inhibition. The end products UTP and CTP bind to the enzyme and reduce its activity when pyrimidine levels are high compared with purines in the cell. This binding at one site affects the linked catalytic site, which helps keep metabolite levels balanced.

ATCase also works as part of the CAD multi-enzyme complex. CAD includes carbamoyl phosphate synthetase II and dihydroorotase in the pyrimidine biosynthesis pathway. Because pyrimidines are needed for DNA synthesis during cell division, blocking ATCase activity can slow tumor growth in cancer.

ATCase Feedback Inhibition in Pyrimidine Synthesis

atcase-feedback-inhibition-pyrimidine-synthesis

ligand binding sites

How Ligands Attach to Proteins

Ligands attach to proteins at specific binding sites on the protein surface. These sites let proteins interact with other molecules or ions and help them carry out important cell functions. Although many possible ligands may be nearby, only a matching ligand can bind to a given protein. A ligand-binding site has a shape and chemical pattern that fit its ligand. This fit comes from the protein’s amino acid chain, which gives the site its structure and reactivity. The ligand stays in place...

protein-protein interfaces

How Proteins Connect to Form Complexes

Proteins connect with other proteins to form complexes that carry out cell functions. These protein-protein interactions, or PPIs, are important for an organism's survival. Most PPIs are held together by many weak, noncovalent chemical forces rather than one strong bond. The shape of the interaction surface helps determine how two proteins fit together. Many globular proteins have surface shapes that match closely and can form many weak bonds. Other PPIs happen between two helices or between a...

conserved binding sites

Predicting Protein Ligand-Binding Pockets

Protein ligand-binding pockets help explain how proteins work. A ligand is a small molecule that binds to a specific spot on a protein. These sites are often conserved in related proteins because they are important for function. When the exact site on a protein surface is not known, it can be predicted. One approach is the energetic method. It examines how amino acid residues interact with the ligand and looks for positions where the binding energy is lowest. Those low-energy regions are...

the equilibrium binding constant and binding strength

the-equilibrium-binding-constant-and-binding-strength

Measuring Protein-Ligand Binding Strength

Protein-ligand binding strength can be measured with the equilibrium binding constant, Kb. This value describes how strongly a protein binds a ligand when the reaction has reached equilibrium. In a bound complex, the protein and ligand are joined as PL, while P and L are the unbound forms. Kb can be determined in two main ways. One approach uses equilibrium concentrations. The other uses reaction kinetics, which are the rates of binding and unbinding. Kb can also be related to the binding rate...

cofactors and coenzymes

Protein Helpers: Cofactors and Coenzymes

Cofactors and coenzymes help enzymes work. Many enzymes need these helper molecules to carry out chemical reactions. Without them, the enzyme may not function properly. A cofactor is a helper molecule that can be either an inorganic ion or an organic molecule. Coenzymes are organic cofactors. They often move between enzymes and help transfer chemical groups or electrons during a reaction. Some cofactors are vitamins or come from vitamins. These molecules are important because they support...

allosteric regulation

How Allosteric Control Changes Enzymes

Allosteric control changes how enzymes work by using a site other than the active site. A small molecule binds to this separate allosteric site and changes the enzyme’s shape. That shape change can alter how well the enzyme binds its substrate and how fast the reaction runs. Many enzymes use this kind of regulation to turn activity up or down when the cell needs it. In some cases, the allosteric molecule acts as an activator and improves enzyme function. In other cases, it acts as an inhibitor...

ligand binding and linkage

Allosteric Proteins: Positive and Negative Effects

Allosteric proteins have more than one ligand binding site. A ligand is a molecule that binds to a protein. When a ligand binds at one site, it can affect binding at the other sites. These sites are called coupled or linked because they influence one another. In enzymes, the site that binds the substrate is the active site. The other site is the regulatory site. When a ligand binds to the regulatory site, it can change the protein’s shape. This conformational change can then alter how the...

cooperative allosteric transitions

Allosteric Switching in Multimeric Proteins

Allosteric switching in multimeric proteins helps explain how ligand binding at one site can change the behavior of the whole protein. In these proteins, each subunit has its own ligand-binding site. When a ligand binds to one subunit, it can cause a shape change that affects the other subunits and their binding sites. This change in shape comes from the protein’s structure, which includes both flexible and stable segments. A molecule that causes the shift is called a modulator. Because the...

phosphorylation

Phosphorylation in Cell Signaling

Phosphorylation is a key step in cell signaling. It changes how a molecule behaves by adding a phosphate group. In many cells, this modification helps control activity, shape, and interactions with other molecules. Phosphorylation is carried out by enzymes called kinases. These enzymes transfer a phosphate group to a target molecule. A phosphatase can remove that phosphate group and reverse the change. Together, kinases and phosphatases help cells turn signals on and off in a controlled way. <br...

protein kinases and phosphatases

Phosphorylation Switches in Protein Control

Protein control often depends on chemical changes that alter a protein’s charge, shape, and conformation. These changes can include phosphorylation, acetylation, glycosylation, nitrosylation, ubiquitination, lipidation, methylation, and proteolysis. In cells, these modifications are usually driven by enzymes. Phosphorylation is one of the most important protein modifications. It adds a phosphate group to a protein and often changes how that protein works. A family of enzymes called kinases...

gtpases and their regulation

GTPase Signaling Switches in Cells

GTPases are cell proteins that act as signaling switches. They help control cell signaling, vesicle transport, cell shape, and cell movement. When these proteins change or stop working properly, disease can result. There are about 40,000 known G-proteins. They are usually grouped into two main types. Small G-proteins have one domain, while large G-proteins have multiple domains. Large G-proteins are also called heterotrimeric G-proteins. They have three subunits: alpha, beta, and gamma. The...

covalently linked protein regulators

How Protein Tags Change Cell Signaling

Proteins can be changed after they are made by adding small chemical tags or small proteins. These post-translational modifications help control protein function and stability when the cell environment changes. Common covalent regulators include methyl, acetyl, and phosphate groups, as well as small proteins such as ubiquitin. About 200 types of covalent regulators have been identified. These tags attach to specific amino acids in a protein. Phosphate groups can attach only to serine,...

protein complexes with interchangeable parts

protein-complexes-with-interchangeable-parts

SCF Ubiquitin Ligase and F-Box Variants

The SCF ubiquitin ligase is a protein complex that uses an F-box protein to help choose which target proteins get marked for destruction. This complex is made of five separate proteins, and each one has a different job. Together, they attach ubiquitin to target proteins so the cell can send those proteins to be degraded. The F-box protein is the part that binds the substrate, or target protein. That binding step lets the ubiquitin-conjugating enzyme reach the target and attach ubiquitin. In...

mechanical protein functions

Protein Force: Cell Movement and Support

Proteins can create and respond to mechanical force in cells. Some proteins generate force, while others are pulled or stretched by it. Proteins such as keratin provide structural support and are subjected to mechanical force. Proteins such as ion pumps help move molecules across cell membranes and can generate mechanical force. Cell movement and muscle contraction depend on turning chemical energy into motion. This often happens through conformational change, which is a shift in a protein’s...

structural protein function

Collagen and the Cell Skeleton

Structural proteins give cells and tissues shape, support, and strength. They help build bones, cartilage, hair, and muscles. Important examples include collagen, actin, myosin, and keratin. Collagen is the most abundant protein in mammals. It is found throughout the body. In skin, ligaments, and tendons, collagen adds tensile strength and elasticity. In bones and teeth, it helps form hard, load-bearing tissue through mineralization. Collagen also does more than provide support. It can...

protein networks

Mapping Protein Interactions

Mapping protein interactions shows how proteins work together in a cell. Many proteins must connect with other proteins to carry out their jobs and keep an organism healthy. These connections can be shown as protein-protein interaction networks, also called protein maps. In these maps, proteins are shown as nodes, or circles. Lines called edges connect two proteins that interact. The network can include stable interactions, such as those in protein complexes, and transient interactions that...

ATCase is a key enzyme in pyrimidine synthesis. It is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to form N-carbamoyl-L-aspartate. This reaction starts the pathway that makes pyrimidines. ATCase is regulated by feedback inhibition. The end products UTP and CTP bind to the enzyme and reduce its activity when pyrimidine levels are high compared with purines in the cell. This binding at one site affects the linked catalytic site, which helps keep...

key terms and concepts

Learn how ATCase is controlled by feedback inhibition from UTP and CTP and how this step helps regulate pyrimidine synthesis and DNA production.

ATCase Feedback Inhibition in Pyrimidine Synthesis | JoVE K12

molecular biology

JoVE Core Molecular Biology showcases the molecular processes of the cell through clear and concise animated video lessons. Additionally, in scientist-in-action videos, these concepts' application is demonstrated through real experiments in modern laboratories.

Arizona Science Standards

Life Science

HS+B.L1

HS+B.L1U1.5

Characteristics of Life

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https://cloudfront.jove.com/files/media/science-education/science-education-thumbs/10647.jpg

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the-tree-of-life-bacteria-archaea-and-eukaryotes

The Tree of Life - Bacteria, Archaea, and Eukaryotes

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Compare and contrast existing models, identify patterns, and use structural and functional evidence to analyze the characteristics of life. Engage in argument about the designation of viruses as non-living based on these characteristics.
EXPLANATION: Students begin to develop patterns of living and non-living organisms in kindergarten and build on detailed characteristics of different classifications of living organisms throughout elementary and middle school. Biology 1 discussions introduce viral particles and viral cycles, building on student understanding of living organisms to engage in an argument regarding the classification of a viral particle as either living or non-living.

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BIO1.LS1.2

Nucleic Acids

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Organization of Genes

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Mutations

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Transcription

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Lesson: Translation
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MicroRNAs

siRNA - Small Interfering RNAs

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piRNA - Piwi-interacting RNAs

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lncRNA - Long Non-coding RNAs

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Protein Folding

Protein Families

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conservation-of-protein-domains-over-different-proteins

Conservation of Protein Domains Over Different Proteins

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Globular and Fibrous Proteins

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Intrinsically Disordered Proteins

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Protein Complex Assembly

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Conjugated Proteins

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Antibody Structure

Phosphorylation

Ligand Binding Sites

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Protein Kinases and Phosphatases

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Conserved Binding Sites

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Covalently Linked Protein Regulators

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The Equilibrium Binding Constant and Binding Strength

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Protein Complexes with Interchangeable Parts

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Ligand Binding and Linkage

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BIO1.LS1.6

ATCase Feedback Inhibition in Pyrimidine Synthesis

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