Alvan Hengge
Utah State University
H-index: 45
North America-United States
About Alvan Hengge
Alvan Hengge, With an exceptional h-index of 45 and a recent h-index of 14 (since 2020), a distinguished researcher at Utah State University, specializes in the field of Enzymology, Physical Organic Chemistry.
His recent articles reflect a diverse array of research interests and contributions to the field:
Sequence–dynamics–function relationships in protein tyrosine phosphatases
SHP-1 Variants Broaden the Understanding of pH-Dependent Activities in Protein Tyrosine Phosphatases
Competitive measurement of β/α naphthyl phosphate catalytic efficiency by phosphatases utilizing quantitative NMR
Correction to “Loop Dynamics and Enzyme Catalysis in Protein Tyrosine Phosphatases”
Insights into the importance of WPD-loop sequence for activity and structure in protein tyrosine phosphatases
Single residue on the WPD-loop affects the pH dependency of catalysis in protein tyrosine phosphatases
Loop dynamics and enzyme catalysis in protein tyrosine phosphatases
Plasmodium falciparum finds the winning combination
Alvan Hengge Information
University | Utah State University |
---|---|
Position | Professor of Chemistry |
Citations(all) | 5553 |
Citations(since 2020) | 931 |
Cited By | 4882 |
hIndex(all) | 45 |
hIndex(since 2020) | 14 |
i10Index(all) | 93 |
i10Index(since 2020) | 24 |
University Profile Page | Utah State University |
Alvan Hengge Skills & Research Interests
Enzymology
Physical Organic Chemistry
Top articles of Alvan Hengge
Sequence–dynamics–function relationships in protein tyrosine phosphatases
Authors
Rory M Crean,Marina Corbella,Ana R Calixto,Alvan C Hengge,Shina Caroline Lynn Kamerlin
Journal
QRB Discovery
Published Date
2023/6/16
Protein tyrosine phosphatases are crucial regulators of cellular signaling. Their activity is regulated by the motion of a conserved loop, the WPD-loop, from a catalytically inactive open to a catalytically active closed conformation. WPD-loop motion optimally positions a catalytically critical residue into the active site, and is directly linked to the turnover number of these enzymes. Crystal structures of chimeric PTPs constructed by grafting parts of the WPD-loop sequence of PTP1B onto the scaffold of YopH showed WPD-loops in a wide-open conformation never previously observed in either parent enzyme. This wide-open conformation has, however, been observed upon binding of small molecule inhibitors to other PTPs, suggesting the potential of targeting it for drug discovery efforts. Here, we have performed simulations of both enzymes and show that there are negligible energetic differences in the chemical step of …
SHP-1 Variants Broaden the Understanding of pH-Dependent Activities in Protein Tyrosine Phosphatases
Authors
Ruidan Shen,Alfie-Louise Brownless,Nikolas Alansson,Marina Corbella,Shina Caroline Lynn Kamerlin,Alvan Hengge
Published Date
2024/1/18
The protein tyrosine phosphatase (PTP) SHP-1 plays an important role in both immune regulation and oncogenesis. This enzyme is part of a broader family of PTPs that all play important regulatory roles in vivo. Common to these enzymes is a highly conserved aspartic acid (D421 in SHP-1) that acts as an acid/base catalysis during the PTP-catalyzed reaction. This residue is located on a mobile loop, the WPD-loop, the dynamical behavior of which is intimately connected to catalytic activity. The SHP-1 WPD-loop variants H422Q, E427A, and S418A have been kinetically characterized and compared to the WT enzyme. These variants exhibit limiting magnitudes of kcat ranging from 43% to 77% of the WT enzyme. However, their pH profiles are significantly broadened in the basic pH range. As a result, above pH 6 the E427A and S418A variants have notably higher turnover numbers than WT SHP-1. Molecular modeling results indicate that the shifted pH dependencies result primarily from changes in solvation and hydrogen-bonding networks that affect the pKa of the D421 residue, explaining the changes in pH-rate profiles for kcat on the basic side. In contrast, a previous study of a noncatalytic residue variant of the PTP YopH, which also exhibited changes in pH dependency, showed that catalytic change arose from mutation-induced changes in conformational equilibria of the WPD-loop. That finding, and the present study, show the existence of distinct strategies for nature to tune the activity of PTPs in particular environments through controlling the pH-dependency of catalysis.
Competitive measurement of β/α naphthyl phosphate catalytic efficiency by phosphatases utilizing quantitative NMR
Authors
Justin Pinkston,Ruidan Shen,Casey R Simons,Alvan C Hengge
Journal
Analytical Biochemistry
Published Date
2022/8/15
The two constitutional isomers of naphthyl phosphate have different steric properties, analogous to those of phosphotyrosine versus phosphoserine/threonine within a peptide or protein. The ratios of their respective rates of hydrolysis, assayed by measuring rates of inorganic phosphate release, have been used to probe the steric requirements around the active sites of many phosphatases in the literature. We report an NMR-based competitive method that is simpler to execute and has other advantages. It directly yields the ratio of catalytic efficiencies (V/K) of the two substrates, a more biologically relevant comparison than the ratio of initial rates (vo) or maximal rates (Vmax). The competitive method ensures that temperature, pH, enzyme and substrate concentrations, and the presence of any potential inhibitors are identical and will not skew the results. The method can be easily applied at any chosen temperature or …
Correction to “Loop Dynamics and Enzyme Catalysis in Protein Tyrosine Phosphatases”
Authors
Rory M Crean,Michal Biler,Marina Corbella,Ana R Calixto,Marc W van der Kamp,Alvan C Hengge,Shina CL Kamerlin
Journal
Journal of the American Chemical Society
Published Date
2022/5/24
Upon further examination of the literature, we observed that the experimental rate for the alkaline hydrolysis of the p-nitrophenyl phosphate (pNPP) dianion likely corresponds to attack at the aromatic ring with C− O cleavage, and not P− O cleavage, due to the resistance of phosphate ester dianions to attack by hydroxide ion. 3, 4 By extension, the reaction with a thiolate nucleophile (analogous to that of these protein tyrosine phosphatases (PTPs)) is even less likely to occur in solution due to the larger size of S compared to O. As this makes it impossible to know what the barrier to a hypothetical uncatalyzed reaction proceeding through P− O cleavage would be, it renders a comparison to the non-enzymatic reaction energetically uninformative.Since the non-enzymatic reaction is not a good reference state, we have used instead the PTP1B-catalyzed reaction (fit to experimental kinetics) as our reference state, and we …
Insights into the importance of WPD-loop sequence for activity and structure in protein tyrosine phosphatases
Authors
Ruidan Shen,Rory M Crean,Keith J Olsen,Marina Corbella,Ana R Calixto,Teisha Richan,Tiago AS Brandão,Ryan D Berry,Alex Tolman,J Patrick Loria,Sean J Johnson,Shina CL Kamerlin,Alvan C Hengge
Journal
Chemical Science
Published Date
2022
Protein tyrosine phosphatases (PTPs) possess a conserved mobile catalytic loop, the WPD-loop, which brings an aspartic acid into the active site where it acts as an acid/base catalyst. Prior experimental and computational studies, focused on the human enzyme PTP1B and the PTP from Yersinia pestis, YopH, suggested that loop conformational dynamics are important in regulating both catalysis and evolvability. We have generated a chimeric protein in which the WPD-loop of YopH is transposed into PTP1B, and eight chimeras that systematically restored the loop sequence back to native PTP1B. Of these, four chimeras were soluble and were subjected to detailed biochemical and structural characterization, and a computational analysis of their WPD-loop dynamics. The chimeras maintain backbone structural integrity, with somewhat slower rates than either wild-type parent, and show differences in the pH …
Single residue on the WPD-loop affects the pH dependency of catalysis in protein tyrosine phosphatases
Authors
Ruidan Shen,Rory M Crean,Sean J Johnson,Shina CL Kamerlin,Alvan C Hengge
Journal
JACS Au
Published Date
2021/4/23
Catalysis by protein tyrosine phosphatases (PTPs) relies on the motion of a flexible protein loop (the WPD-loop) that carries a residue acting as a general acid/base catalyst during the PTP-catalyzed reaction. The orthogonal substitutions of a noncatalytic residue in the WPD-loops of YopH and PTP1B result in shifted pH-rate profiles from an altered kinetic pKa of the nucleophilic cysteine. Compared to wild type, the G352T YopH variant has a broadened pH-rate profile, similar activity at optimal pH, but significantly higher activity at low pH. Changes in the corresponding PTP1B T177G variant are more modest and in the opposite direction, with a narrowed pH profile and less activity in the most acidic range. Crystal structures of the variants show no structural perturbations but suggest an increased preference for the WPD-loop-closed conformation. Computational analysis confirms a shift in loop conformational …
Loop dynamics and enzyme catalysis in protein tyrosine phosphatases
Authors
Rory M Crean,Michal Biler,Marc W van der Kamp,Alvan C Hengge,Shina CL Kamerlin
Journal
Journal of the American Chemical Society
Published Date
2021/3/4
Protein tyrosine phosphatases (PTPs) play an important role in cellular signaling and have been implicated in human cancers, diabetes, and obesity. Despite shared catalytic mechanisms and transition states for the chemical steps of catalysis, catalytic rates within the PTP family vary over several orders of magnitude. These rate differences have been implied to arise from differing conformational dynamics of the closure of a protein loop, the WPD-loop, which carries a catalytically critical residue. The present work reports computational studies of the human protein tyrosine phosphatase 1B (PTP1B) and YopH from Yersinia pestis, for which NMR has demonstrated a link between their respective rates of WPD-loop motion and catalysis rates, which differ by an order of magnitude. We have performed detailed structural analysis, both conventional and enhanced sampling simulations of their loop dynamics, as well as …
Plasmodium falciparum finds the winning combination
Authors
Alvan C Hengge
Journal
Journal of Biological Chemistry
Published Date
2021/1/1
After 3 years of laboratory drug pressure in the presence of a picomolar inhibitor, the parasite Plasmodium falciparum developed a combination strategy of gene amplification and mutation to regain viability. The mutation observed led to a dysfunctional enzyme, but new research reveals the clever mechanism behind its success. Not that we needed a reminder of nature's creativity in the time of a pandemic.
Significant loop motions in the SsoPTP protein tyrosine phosphatase allow for dual general acid functionality
Authors
Justin Pinkston,Jihye Jo,Keith J Olsen,Drake Comer,Charsti A Glaittli,J Patrick Loria,Sean J Johnson,Alvan C Hengge
Journal
Biochemistry
Published Date
2021/9/8
Conformational dynamics are important factors in the function of enzymes, including protein tyrosine phosphatases (PTPs). Crystal structures of PTPs first revealed the motion of a protein loop bearing a conserved catalytic aspartic acid, and subsequent nuclear magnetic resonance and computational analyses have shown the presence of motions, involved in catalysis and allostery, within and beyond the active site. The tyrosine phosphatase from the thermophilic and acidophilic Sulfolobus solfataricus (SsoPTP) displays motions of its acid loop together with dynamics of its phosphoryl-binding P-loop and the Q-loop, the first instance of such motions in a PTP. All three loops share the same exchange rate, implying their motions are coupled. Further evidence of conformational flexibility comes from mutagenesis, kinetics, and isotope effect data showing that E40 can function as an alternate general acid to protonate the …
Modeling the alkaline hydrolysis of diaryl sulfate diesters: A mechanistic study
Authors
Klaudia Szeler,Nicholas H Williams,Alvan C Hengge,Shina CL Kamerlin
Journal
The Journal of Organic Chemistry
Published Date
2020/4/20
Phosphate and sulfate esters have important roles in regulating cellular processes. However, while there has been substantial experimental and computational investigation of the mechanisms and the transition states involved in phosphate ester hydrolysis, there is far less work on sulfate ester hydrolysis. Here, we report a detailed computational study of the alkaline hydrolysis of diaryl sulfate diesters, using different DFT functionals as well as mixed implicit/explicit solvation with varying numbers of explicit water molecules. We consider the impact of the computational model on computed linear free-energy relationships (LFER) and the nature of the transition states (TS) involved. We obtain good qualitative agreement with experimental LFER data when using a pure implicit solvent model and excellent agreement with experimental kinetic isotope effects for all models used. Our calculations suggest that sulfate diester …
Alvan Hengge FAQs
What is Alvan Hengge's h-index at Utah State University?
The h-index of Alvan Hengge has been 14 since 2020 and 45 in total.
What are Alvan Hengge's top articles?
The articles with the titles of
Sequence–dynamics–function relationships in protein tyrosine phosphatases
SHP-1 Variants Broaden the Understanding of pH-Dependent Activities in Protein Tyrosine Phosphatases
Competitive measurement of β/α naphthyl phosphate catalytic efficiency by phosphatases utilizing quantitative NMR
Correction to “Loop Dynamics and Enzyme Catalysis in Protein Tyrosine Phosphatases”
Insights into the importance of WPD-loop sequence for activity and structure in protein tyrosine phosphatases
Single residue on the WPD-loop affects the pH dependency of catalysis in protein tyrosine phosphatases
Loop dynamics and enzyme catalysis in protein tyrosine phosphatases
Plasmodium falciparum finds the winning combination
...
are the top articles of Alvan Hengge at Utah State University.
What are Alvan Hengge's research interests?
The research interests of Alvan Hengge are: Enzymology, Physical Organic Chemistry
What is Alvan Hengge's total number of citations?
Alvan Hengge has 5,553 citations in total.
What are the co-authors of Alvan Hengge?
The co-authors of Alvan Hengge are Daniel Herschlag, Zhong-Yin Zhang, John M Denu, Hua Guo, Kamerlin SC*, Natasa Mitic.