Sebastiana Angelaccio

Istituto Pasteur

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Francesco Bossa

Sapienza University of Rome

Roberto Contestabile

Sapienza University of Rome

Stefano Pascarella

Sapienza University of Rome

Verne Schirch

Virginia Commonwealth University

Donatella Barra

Sapienza University of Rome

Martino L. di Salvo

Sapienza University of Rome

Angela Tramonti

Institute of Molecular Biology and Pathology

Isabel Nogués

National Research Council

Valerio Consalvi

Sapienza University of Rome

Rita Florio

European Brain Research Institute

Cooperative Institutions

Sapienza University of Rome

Virginia Commonwealth University

Institute of Molecular Biology and Pathology

Istituto Pasteur

Virginia Commonwealth University Medical Center

National Research Council

Cardiff University

Institute of Bioorganic Chemistry, Polish Academy of Sciences

National Academies of Sciences, Engineering, and Medicine

Istituto di Genetica Molecolare

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Structural and kinetic properties of serine hydroxymethyltransferase from the halophytic cyanobacterium Aphanothece halophytica provide a rationale for salt tolerance

International Journal of Biological Macromolecules (2020)

Isabel Nogués Angela Tramonti Sebastiana Angelaccio M. Ruszkowski B. Sekula

Serine hydroxymethyltransferase

Betaine

Photorespiration

Glycine cleavage system

Cyanate

10.1016/j.ijbiomac.2020.05.081

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Citations (8)

The Origin of Substrate and Reaction Specificity in Serine Hydroxymethyltransferase

Elsevier eBooks (1991)

Verne Schirch Sebastiana Angelaccio Simona Pascarella Elena Fattori Francesco Bossa

Serine hydroxymethyltransferase

10.1016/b978-0-08-040820-0.50072-8

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Citations (3)

Insights into the substrate specificity, structure, and dynamics of plant histidinol-phosphate aminotransferase (HISN6)

Plant Physiology and Biochemistry (2023)

Maria Rutkiewicz Isabel Nogués Wojciech Witek Sebastiana Angelaccio Roberto Contestabile

Histidinol-phosphate aminotransferase is the sixth protein (hence HISN6) in the histidine biosynthetic pathway in plants. HISN6 is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that catalyzes the reversible conversion of imidazole acetol phosphate into L-histidinol phosphate (HOLP). Here, we show that plant HISN6 enzymes are closely related to the orthologs from Chloroflexota. The studied example, HISN6 from Medicago truncatula (MtHISN6), exhibits a surprisingly high affinity for HOLP, which is much higher than reported for bacterial homologs. Moreover, unlike the latter, MtHISN6 does not transaminate phenylalanine. High-resolution crystal structures of MtHISN6 in the open and closed states, as well as the complex with HOLP and the apo structure without PLP, bring new insights into the enzyme dynamics, pointing at a particular role of a string-like fragment that oscillates near the active site and participates in the HOLP binding. When MtHISN6 is compared to bacterial orthologs with known structures, significant differences arise in or near the string region. The high affinity of MtHISN6 appears linked to the particularly tight active site cavity. Finally, a virtual screening against a library of over 1.3 mln compounds revealed three sites in the MtHISN6 structure with the potential to bind small molecules. Such compounds could be developed into herbicides inhibiting plant HISN6 enzymes absent in animals, which makes them a potential target for weed control agents.

Transferase

10.1016/j.plaphy.2023.02.017

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Structural basis of methotrexate and pemetrexed action on serine hydroxymethyltransferases revealed using plant models

Scientific Reports (2019)

M. Ruszkowski B. Sekula Agnieszka Ruszkowska Roberto Contestabile Isabel Nogués

Abstract Serine hydroxymethyltransferases (SHMTs) reversibly transform serine into glycine in a reaction accompanied with conversion of tetrahydrofolate (THF) into 5,10-methylene-THF (5,10-meTHF). In vivo , 5,10-meTHF is the main carrier of one-carbon (1C) units, which are utilized for nucleotide biosynthesis and other processes crucial for every living cell, but hyperactivated in overproliferating cells (e.g. cancer tissues). SHMTs are emerging as a promising target for development of new drugs because it appears possible to inhibit growth of cancer cells by cutting off the supply of 5,10-meTHF. Methotrexate (MTX) and pemetrexed (PTX) are two examples of antifolates that have cured many patients over the years but target different enzymes from the folate cycle (mainly dihydrofolate reductase and thymidylate synthase, respectively). Here we show crystal structures of MTX and PTX bound to plant SHMT isozymes from cytosol and mitochondria—human isozymes exist in the same subcellular compartments. We verify inhibition of the studied isozymes by a thorough kinetic analysis. We propose to further exploit antifolate scaffold in development of SHMT inhibitors because it seems likely that especially polyglutamylated PTX inhibits SHMTs in vivo . Structure-based optimization is expected to yield novel antifolates that could potentially be used as chemotherapeutics.

Pemetrexed

Basis (linear algebra)

10.1038/s41598-019-56043-4

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Citations (13)

Primary Structure Studies on Serine Hydroxymethyltransferase

Springer eBooks (1987)

Donatella Barra Filippo Martini Sebastiana Angelaccio Stefano Pascarella Francesco Bossa

Serine hydroxymethyltransferase

Tetramer

Moiety

Protein primary structure

10.1007/978-1-4613-1787-6_78

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Mutagenesi sito-specifica nello studio delta serina idrossimetiltrasferasi

RENDICONTI LINCEI (1990)

Elena Fattori Sebastiana Angelaccio Stefano Pascarella Francesco Bossa Donatella Barra

Source

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Extremophilic SHMTs: From Structure to Biotechnology

BioMed Research International (2013)

Sebastiana Angelaccio

Recent advances in molecular and structural biology have improved the availability of virtually any biocatalyst in large quantity and have also provided an insight into the detailed structure-function relationships of many of them. These results allowed the rational exploitation of biocatalysts for use in organic synthesis. In this context, extremophilic enzymes are extensively studied for their potential interest for many biotechnological and industrial applications, as they offer increased rates of reactions, higher substrate solubility, and/or longer enzyme half-lives at the conditions of industrial processes. Serine hydroxymethyltransferase (SHMT), for its ubiquitous nature, represents a suitable model for analyzing enzyme adaptation to extreme environments. In fact, many SHMT sequences from Eukarya, Eubacteria and Archaea are available in data banks as well as several crystal structures. In addition, SHMT is structurally conserved because of its critical metabolic role; consequently, very few structural changes have occurred during evolution. Our research group analyzed the molecular basis of SHMT adaptation to high and low temperatures, using experimental and comparative in silico approaches. These structural and functional studies of SHMTs purified from extremophilic organisms can help to understand the peculiarities of the enzyme activity at extreme temperatures, indicating possible strategies for rational enzyme engineering.

Serine hydroxymethyltransferase

Extreme environment

Extremophile

Protein Engineering

Structural genomics

10.1155/2013/851428

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Citations (20)

Role of Y65 and E57 in Escherichia coli Serine Hydroxymethyltransferase

Birkhäuser Basel eBooks (2000)

Sebastiana Angelaccio Roberto Contestabile Paolo Di Giovine Francesco Bossa Verne Schirch

The crystal structures of serine hydroxymethyltransferase from three different sources have recently been solved. Inspection of the active site reveals that, besides K229, whose role as catalytic base had been ruled out, either E57 or Y65 may be the putative active-site proton exchanger required for catalysis. Two mutant forms of theE. co/ienzyme, E57Q and Y65F, were produced and their catalytic properties studied. The results show that neither E57 nor Y65 is the elusive catalytic base. The Y65F mutation substantially reduced Keatand Kmfor cleavage of β-hydroxyamino acids, although the catalytic efficiency was unaffected. A possible role of Y65 in the conformational change that is thought to take place upon binding of substrates is proposed.

Serine hydroxymethyltransferase

Cleavage (geology)

Base (topology)

10.1007/978-3-0348-8397-9_27

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X-RAY CRYSTAL STRUCTURE AT 2.7 ANGSTROMS RESOLUTION OF TERNARY COMPLEX BETWEEN THE Y65F MUTANT OF E-COLI SERINE HYDROXYMETHYLTRANSFERASE, GLYCINE AND 5-FORMYL TETRAHYDROFOLATE

Roberto Contestabile Sebastiana Angelaccio Francesco Bossa H.T. Wright Neel Scarsdale

Serine hydroxymethyltransferase

Angstrom

10.2210/pdb1eqb/pdb

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