Structural and Computational Insights into Transketolase-like 1 (TKTL-1): Distinction from TKT and Implications for Cancer Metabolism and Therapeutic Targeting

TL;DR

This paper explores the structure and function of TKTL-1, a protein linked to cancer metabolism, and suggests ways to target it for drug development.

Contribution

The study provides a homology model and computational framework for understanding TKTL-1's structure and function, distinct from TKT.

Findings

A homology model of TKTL-1 was created and validated against TKT.

TKTL-1 shows reduced affinity for TDP compared to TKT, indicating functional divergence.

Predictive scaffolds for modulating TKTL-1 were proposed based on conserved residues and receptor surfaces.

Abstract

Transketolase-like protein 1 (TKTL-1) has been implicated in altered cancer metabolism, yet its structure and molecular function remain poorly understood. In this study, we established a homology model of TKTL-1 using multiple templates and validated it through sequence alignment and structural comparison with the canonical transketolase (TKT). Binding-site identification was performed using CASTp, receptor cavity mapping, and blind docking, all of which consistently pointed to a conserved region involving interactive residues shared between TKT and TKTL-1. Comparative docking revealed the reduced affinity of TKTL-1 for TDP, supporting functional divergence between TKTL-1 and TKT. We further analyzed conserved residues and receptor surfaces, which enabled us to propose predictive scaffolds as potential modulators of TKTL-1. While these scaffolds remain theoretical, they provide a computational framework to guide future pharmacophore modeling, molecular dynamics simulations, and experimental validation. Together, our study highlights the structural features of TKTL-1, establishes its key differences from TKT, and lays the groundwork for future drug discovery efforts targeting cancer metabolism.

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