Evidence map›Paper›PMID 40537411›Full record

ArticleAngewandte Chemie (International ed. in English)2025

Is a Malleable Active Site Loop the Key to High Substrate Promiscuity? Hybrid, Biocatalytic Route to Structurally Diverse Taxoid Side Chains with Remarkable Dual Stereocontrol.

Gaurav P Kudalkar, Florian Leidner, Nivesh Kumar, Jared L Hass, Peter Madzelan, Douglas R Powell, Victor W Day, Pierre Le Magueres, Joseph D Ferrara, Lee M Daniels and 6 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Angewandte Chemie (International ed. in English), 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

16 authors.

Gaurav P Kudalkar *Department of Chemistry, University of Nebraska, Lincoln, NE, 68588-0304, USA.
Florian Leidner *Theoretical and Computational Biophysics, Max-Planck Institute for Multidisciplinary Sciences, Göttingen, 37077, Germany.
Nivesh KumarDepartment of Chemistry, University of Nebraska, Lincoln, NE, 68588-0304, USA.
Jared L HassDepartment of Chemistry, University of Nebraska, Lincoln, NE, 68588-0304, USA.
Peter MadzelanDepartment of Biochemistry, University of Nebraska, Lincoln, NE, 68588-0664, USA.
Douglas R PowellDepartment of Chemistry and Biochemistry, University of Oklahoma, Norman, OK, 73019, USA.
Victor W DayX-Ray Crystallography Facility, University of Kansas, Lawrence, KS, 66045, USA.
Pierre Le MagueresRigaku Americas Corporation, The Woodlands, TX, 77381, USA.
Joseph D FerraraRigaku Americas Corporation, The Woodlands, TX, 77381, USA.
Lee M DanielsRigaku Americas Corporation, The Woodlands, TX, 77381, USA.
Akihito YamanoRigaku Corporation, Tokyo, 196-866, Japan.
Sho ItoRigaku Corporation, Tokyo, 196-866, Japan.
Wei NiuDepartment of Chemical and Biomolecular Engineering, University of Nebraska, Lincoln, NE, 68588-0643, USA.
Helmut GrubmüllerTheoretical and Computational Biophysics, Max-Planck Institute for Multidisciplinary Sciences, Göttingen, 37077, Germany.
Mark A WilsonDepartment of Biochemistry, University of Nebraska, Lincoln, NE, 68588-0664, USA.
David B BerkowitzDepartment of Chemistry, University of Nebraska, Lincoln, NE, 68588-0304, USA.ORCID 0000-0001-7550-0112

Funding

A Synchrotron Radiation Structural Biology ResourcesP30GM133894 · NIGMS · STANFORD UNIVERSITY · PI Aina E. Cohen, KEITH O HODGSON · 2020 to 2026
$43.3M
Targeted mass spectrometry approaches to understand CART processing and recepter interactionsP20GM113126 · NIGMS · UNIVERSITY OF NEBRASKA LINCOLN · PI POWERS, ROBERT · 2016 to 2025
$20.8M
EXTRAMURAL RES FACILITIES CONSTRC06RR016544 · NCRR · UNIVERSITY OF NEBRASKA LINCOLN · PI PAUL, PREM S · 2001 to 2001
$2.0M
National Institutes of Health, National Institute of General Medical Sciences P30GM133894NCRR NIH HHS C06 RR016544NIGMS NIH HHS P20 GM113126NIGMS NIH HHS P30 GM133894NIH HHS SIG-1-510-RR-06307NSF CBET-2023250U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences DE-AC02-76SF00515
6 · The paper itself

Abstract

These studies reveal the first structure of Clostridium acetobutylicum alcohol dehydrogenase (CaADH), a protein exhibiting remarkable substrate promiscuity and stereochemical fidelity. The CaADH enzyme is utilized here for synthesizing 20 potential aryl isoserine side chains for the Taxotere family of tubulin-binding chemotherapeutics. The approach involves dynamic reductive kinetic resolution (DYRKR) upon the corresponding α-chloro-β-keto esters, showing high D-syn stereoselectivity, including those leading to the clinically relevant milataxel (Ar = 2-furyl) and simotaxel (Ar = 2-thienyl) side chains. Furthermore, various cross-coupling chemistries performed on the p-bromophenyl isoserine side chain significantly enhance the structural diversity of the taxoid side chain library obtained (16 additional taxoid side chains). The CaADH structure is notable: (i) the nicotinamide cofactor is bound in an anti-conformation, with the amide carbonyl occupying the ketone binding pocket, and (ii) a flexible loop near the active site likely contributes to the remarkable substrate promiscuity observed in CaADH. We present our perspective on the dynamic nature of the CaADH active site through molecular dynamics simulation, proposing a halogen bonding model as a potential mechanism for the remarkable selectivity for an (S)-configured C─Cl bond, in addition to the D-facial selectivity, demonstrated across 20 diverse substrates by this remarkable short-chain dehydrogenase enzyme.

Indexed as

Alcohol DehydrogenaseClostridium acetobutylicumBiocatalysisCatalytic DomainStereoisomerismSubstrate SpecificityAlcohol DehydrogenaseClostridium acetobutylicum alcohol dehydrogenase (CaADH)Dynamic reductive kinetic resolution (DYRKR)Flexible loopHalogen bondingTaxotere side chains

Identifiers

PMID40537411
PMCPMC12289324

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC-ND
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.