title: E2 - Dihydrolipoamide S-Acetyltransferase
category: protein
E2 Dihydrolipoamide S Acetyltransferase is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes. [@blass2000]
title: E2 - Dihydrolipoamide S-Acetyltransferase
category: protein
E2 Dihydrolipoamide S Acetyltransferase is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes. [@blass2000]
<div class="infobox infobox-protein"> [@salker2012]
<table> [@liu2008]
<tr><th colspan="2" style="background:#e8f4f8; text-align:center; font-size:1.1em;">Dihydrolipoamide S-Acetyltransferase</th></tr> [@klun2019]
<tr><td><strong>Protein Name</strong></td><td>E2 (DLAT)</td></tr> [@xie2011]
<tr><td><strong>Gene</strong></td><td>[DLAT](/genes/dlat)</td></tr> [@sheu2019]
<tr><td><strong>UniProt ID</strong></td><td>[P10515](https://www.uniprot.org/uniprot/P10515)</td></tr>
<tr><td><strong>PDB ID</strong></td><td>1QAA, 2D1J, 3l1c</td></tr>
<tr><td><strong>Molecular Weight</strong></td><td>70 kDa (670 amino acids)</td></tr>
<tr><td><strong>Subcellular Localization</strong></td><td>Mitochondrial matrix</td></tr>
<tr><td><strong>Protein Family</strong></td><td>2-oxoacid dehydrogenase complex family</td></tr>
<tr><td><strong>Enzyme Commission</strong></td><td>EC 2.3.1.12</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">Alzheimer</a>, <a href="/wiki/carcinoma" style="color:#ef9a9a">Carcinoma</a>, <a href="/wiki/ms" style="color:#ef9a9a">Ms</a>, <a href="/wiki/parkinson" style="color:#ef9a9a">Parkinson</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">46 edges</a></td>
</tr>
</table>
</div>
Dihydrolipoamide S-Acetyltransferase (DLAT, also known as E2 component) is the catalytic core enzyme of the [pyruvate dehydrogenase complex (PDC)](/mechanisms/pyruvate-dehydrogenase-complex), one of the most important metabolic enzyme complexes in cellular metabolism. DLAT catalyzes the transfer of the acetyl group from acetyl-dihydrolipoamide to [coenzyme A (CoA)](/entities/coenzyme-a), forming [acetyl-CoA](/entities/acetyl-coa) and regenerating dihydrolipoamide. This reaction is a critical step linking [glycolysis](/mechanisms/glycolysis) to the [citric acid cycle (TCA cycle)](/mechanisms/citric-acid-cycle), making DLAT essential for cellular energy production through [oxidative phosphorylation](/mechanisms/oxidative-stress-neurodegeneration).
The pyruvate dehydrogenase complex is a large multienzyme assembly consisting of multiple copies of three enzymatic components: E1 (pyruvate dehydrogenase, encoded by [PDHA1](/genes/pdha1)/[PDHA2](/genes/pdha2)), E2 (DLAT), and E3 (dihydrolipoamide dehydrogenase, encoded by [DLD](/genes/dld)). DLAT forms the structural and catalytic core of this complex, organizing the other components into a precise supramolecular structure that ensures efficient substrate channeling and metabolic regulation.
DLAT adopts a distinctive cubic symmetry, forming a 24-mer core structure that represents one of the largest known enzymatic assemblies in cellular metabolism. The protein consists of three distinct domains connected by flexible linker regions:
The catalytic mechanism of DLAT involves a ping-pong bi-bi ordered ternary complex mechanism:
The 24-mer structure allows multiple simultaneous reactions, dramatically increasing the overall throughput of the complex. Each vertex of the cube can catalyze the reaction independently, providing a remarkable example of evolutionary optimization of metabolic efficiency.
DLAT is essential for aerobic energy metabolism in all eukaryotes and many prokaryotes. The pyruvate dehydrogenase complex sits at the crossroads of carbohydrate metabolism, converting pyruvate (the end product of glycolysis) into acetyl-CoA, the fuel for the TCA cycle. This conversion is irreversible and represents a major regulatory point in cellular metabolism.
Key metabolic functions include:
DLAT activity is tightly regulated through multiple mechanisms:
DLAT has emerged as a significant player in [Alzheimer's disease (AD)](/diseases/alzheimers-disease) pathogenesis:
Metabolic dysfunction: Multiple studies have documented reduced DLAT expression and activity in [AD brain tissue](/brain-regions/hippocampus), particularly in the [hippocampus](/brain-regions/hippocampus) and [cerebral cortex](/brain-regions/cortex). This reduction contributes to cerebral glucose hypometabolism, a hallmark of AD that precedes clinical symptoms by decades.
Mechanisms linking DLAT to AD:
DLAT alterations are also relevant to [Parkinson's disease (PD)](/diseases/parkinsons-disease):
DLAT and other PDC components have been studied as biomarkers:
Several therapeutic strategies target DLAT/PDH:
DLAT (dihydrolipoamide S-acetyltransferase) is the catalytic core of the pyruvate dehydrogenase complex, essential for converting pyruvate to acetyl-CoA and linking glycolysis to oxidative metabolism. In neurodegenerative diseases, particularly Alzheimer's disease, DLAT dysfunction contributes to cerebral hypometabolism and neuronal loss. Understanding DLAT regulation and developing therapeutic strategies to maintain its function represents an important frontier in treating neurodegenerative conditions characterized by metabolic deficits.
The study of E2 Dihydrolipoamide S Acetyltransferase has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.