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Related Concept Videos

Allosteric Proteins-ATCase01:19

Allosteric Proteins-ATCase

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Binding sites linkages can regulate a protein's function.  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  N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
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Allosteric regulation of enzymes occurs when the binding of an effector molecule to a site that is different from the active site causes a change in the enzymatic activity. This alternate site is called an allosteric site, and an enzyme can contain more than one of these sites. Allosteric regulation can either be positive or negative, resulting in an increase or decrease in enzyme activity. Most enzymes that display allosteric regulation are metabolic enzymes involved in the degradation or...
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Ligand Binding and Linkage00:49

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Allosteric proteins have more than one ligand binding site; the binding of a ligand to any of these sites influences the binding of ligands to the other sites. When a protein is allosteric, its binding sites are called coupled or linked.  In the case of enzymes, the site that binds to the substrate is known as the active site and the other site is known as the regulatory site. When a ligand binds to the regulatory site, this leads to conformational changes in the protein that can influence...
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In animals, the mitochondrial F1F0 ATP synthase is the key protein that synthesizes ATP molecules through a complex catalytic mechanism. While the nuclear genome encodes the majority of ATP synthase subunits, the mitochondrial genome encodes some of the enzyme's most critical components. The formation of this multi-subunit enzyme is a complex multi-step process regulated at the level of transcription, translation, and assembly. Defects in one or more of these steps can result in decreased...
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Related Experiment Video

Updated: Jul 17, 2025

Deacetylation Assays to Unravel the Interplay between Sirtuins SIRT2 and Specific Protein-substrates
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Deciphering the Allosteric Activation Mechanism of SIRT6 Using Molecular Dynamics Simulations.

Zhiyuan Zhao1, Jintong Du1,2, Yu Du1

  • 1Department of Medicinal Chemistry and Key Laboratory of Chemical Biology of Natural Products (MOE), School of Pharmaceutical Science, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong, China.

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PubMed
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Molecular dynamics simulations reveal how SIRT6 recognizes substrates and is activated. Fatty acids and synthetic activators stabilize key interactions, guiding the design of new SIRT6 activators for genomic stability and metabolism.

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • SIRT6, an NAD+-dependent deacetylase, is crucial for genomic stability and metabolism.
  • SIRT6 exhibits substrate preference for fatty acyl hydrolysis over deacetylation and is activated by fatty acids.
  • Mechanisms of SIRT6 substrate recognition and activation by small molecules remain unclear.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying SIRT6 substrate recognition and activation.
  • To investigate how fatty acids and synthetic activators modulate SIRT6 activity.

Main Methods:

  • Extensive molecular dynamic simulations were employed.
  • Analysis of protein-substrate and protein-cofactor interactions.

Main Results:

  • Myristoylated substrate binding stabilizes NAD+ conformation, unlike acetyl-lysine substrate binding.
  • Myristic acid allosterically enhances SIRT6 activity by stabilizing NAD+ and substrate binding.
  • Synthetic activators (UBCS039, MDL-801, 12q) stabilize NAD+-His131 interactions, similar to fatty acids.

Conclusions:

  • A novel allosteric activation mechanism for SIRT6 involving substrate and cofactor interactions is proposed.
  • Understanding these interactions is key for rational design of novel SIRT6 activators.
  • This work provides insights into modulating SIRT6 for therapeutic applications in genomic stability and metabolism.