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Allosteric Proteins-ATCase01:19

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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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ATP2A3 in Primary Aldosteronism: Machine Learning-Based Discovery and Functional Validation.

Zhuolun Sun1, Elisabeth Kemter2, Yingxian Pang1

  • 1Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Germany (Z.S., Y.P., M.B., M.R., T.A.W.).

Hypertension (Dallas, Tex. : 1979)
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Summary
This summary is machine-generated.

Machine learning identified ATP2A3 as a key gene in aldosterone-producing adenomas (APAs). This gene regulates CYP11B2 expression and aldosterone production, offering potential new therapeutic targets for primary aldosteronism.

Keywords:
adenomaadrenal glandsaldosteronecalcium-transporting ATPasesgene expression profilinghyperaldosteronismmineralocorticoids

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Area of Science:

  • Endocrinology
  • Bioinformatics
  • Molecular Biology

Background:

  • Aldosterone-producing adenomas (APAs) are a primary cause of aldosteronism, potentially leading to cardiovascular issues.
  • Machine learning (ML) offers advanced bioinformatics tools for identifying disease biomarkers in biomedical research.

Purpose of the Study:

  • To utilize ML for discovering novel biomarkers in APAs.
  • To elucidate new pathophysiological mechanisms underlying APAs.

Main Methods:

  • Applied two ML algorithms to RNA sequencing data to identify APA feature genes.
  • Validated findings using APA tissues, spatial transcriptomics, pig adrenal glands, and in vitro cell assays.

Main Results:

  • Identified ATP2A3 as a key APA feature gene, confirmed by spatial transcriptomics.
  • ATP2A3 upregulation observed in APAs; angiotensin II increased its expression in human cells.
  • ATP2A3 silencing reduced CYP11B2 expression and aldosterone secretion, modulated by calcium (Ca2+).
  • Dietary sodium restriction in pigs increased ATP2A3 levels.

Conclusions:

  • ATP2A3 is highly expressed in APAs and acts as a critical regulator of CYP11B2 and aldosterone production.
  • Findings suggest ATP2A3 as a potential therapeutic target for primary aldosteronism.