Jirí Jirácek

Jirí Jirácek
The Czech Academy of Sciences | AVCR · Institute of Organic Chemistry and Biochemistry

PhD

About

145
Publications
14,865
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2,649
Citations
Additional affiliations
January 1998 - present
The Czech Academy of Sciences
Position
  • Head of the Research Group

Publications

Publications (145)
Article
Chiral CE methods were developed for elucidation of l‐ or d‐configuration of tyrosine residue in antimicrobial dipeptide β‐alanyl‐tyrosine (β‐Ala‐Tyr) isolated from hemolymph of larvae of fleshfly Neobellieria bullata and for evaluation of enantiopurity of its synthetic isomers (β‐Ala‐d‐Tyr and β‐Ala‐l‐Tyr), and enantiomers of their amidated and ac...
Article
Preptin is a 34-amino-acid-long peptide derived from the E-domain of a precursor of insulin-like growth factor 2 (pro-IGF2) with bone-anabolic and insulin secretion amplifying properties. Here, we describe the synthesis, structures, and biological activities of six shortened analogues of human preptin. Eight- and nine-amino-acid-long peptide amides...
Article
Full-text available
The problem of a growing resistance of bacteria and other microorganisms to conventional antibiotics gave rise to a search for new potent antimicrobial agents. Insect antimicrobial peptides (AMPs) seem to be promising novel potential anti-infective therapeutics. The dipeptide β-alanyl-tyrosine (β-Ala-Tyr) is one of the endogenous insect toxins exhi...
Article
We adapted a radioligand receptor binding assay for measuring insulin levels in unknown samples. The assay enables rapid and accurate determination of insulin concentrations in experimental samples, such as from insulin-secreting cells. The principle of the method is based on the binding competition of insulin in a measured sample with a radiolabel...
Poster
Full-text available
Design of insulin receptor B isoform selective analogue.
Article
Full-text available
The members of the insulin superfamily are well conserved across the evolution tree. We recently showed that four viruses in the Iridoviridae family possess genes that share high similarity with human insulin and IGF-1. By chemically synthesizing single chain (sc, IGF-1 like) forms of these viral insulin/IGF-1 like peptides (VILPs), we previously s...
Article
Full-text available
Multi-orthogonal molecular scaffolds can be applied as core structures of bioactive compounds. Here, we prepared four tri-orthogonal scaffolds based on adamantane or proline skeletons. The scaffolds were used for the solid-phase synthesis of model insulin mimetics bearing two different peptides on the scaffolds. We found that adamantane-derived com...
Article
OBJECTIVE: Members of the insulin/insulin-like growth factor (IGF) superfamily are well conserved across the evolutionary tree. We recently showed that four viruses in the Iridoviridae family possess genes that encode proteins highly homologous to human insulin/IGF-1. Using chemically synthesized single-chain (sc), i.e., IGF-1-like, forms of the vi...
Article
Full-text available
Insulin is produced and stored inside the pancreatic β-cell secretory granules, where it is assumed to form Zn ²⁺ -stabilized oligomers. However, the actual storage forms of this hormone and the impact of zinc ions on insulin production in vivo are not known. Our initial X-ray fluorescence experiment on granules from native Langerhans islets and in...
Article
Full-text available
Preparation of both 125 I-labeled insulin and insulin-like growth factor 1 (IGF-1) was critical because it enabled a detailed characterization of binding properties of these important hormones towards their cognate transmembrane receptors. Binding modes of hundreds of hormone derivatives were analyzed using competition radioligand binding assays. T...
Article
Full-text available
Insulin-like growth factors 2 and 1 (IGF2 and IGF1) and insulin are closely related hormones that are responsible for the regulation of metabolic homeostasis, development and growth of the organism. Physiological functions of insulin and IGF1 are relatively well-studied, but information about the role of IGF2 in the body is still sparse. Recent dis...
Preprint
Full-text available
Members of the insulin/IGF superfamily are well conserved across the evolutionary tree. We recently showed that four viruses in the Iridoviridae family possess genes that encode proteins highly homologous to human insulin/IGF-1. Using chemically synthesized single chain (sc), i.e. IGF-1-like, forms of the viral insulin/IGF-1 like peptides (VILPs),...
Article
Full-text available
A series of N-terminally Fmoc-protected linkers of the general formula Fmoc-X-CO-O-Y-COOH have been prepared, where X is -NH-CH2 -CH2 - or -p-(aminomethyl)phenyl- and Y is -(CH2 )n - (n is 1 or 4) or -p-(methyl)phenyl-. These linkers can easily be covalently attached via their C-terminal carboxyl group to a resin bearing a free amino group. After c...
Article
Full-text available
Structural details of changes accompanying interaction between insulin-related hormones and their binding partners are often enigmatic. Here, cross-linking/mass spectrometry could complement structural techniques and reveal details of these protein-protein interfaces. We used such approach to clarify missing structural description of the interface...
Article
Full-text available
Information on how insulin and insulin-like growth factors 1 and 2 (IGF-1 and -2) activate insulin receptors (IR-A and -B) and the IGF-1 receptor (IGF-1R) is crucial for understanding the difference in the biological activities of these peptide hormones. Cryo-EM studies have revealed that insulin uses its binding sites 1 and 2 to interact with IR-A...
Article
Full-text available
Cone snails have evolved a variety of insulin-like molecules that may help with the development of better treatments for diabetes.
Article
A new method, pressure assisted partial filling affinity capillary electrophoresis, has been developed to study noncovalent molecular interactions of the hexamer of human insulin (HI) with biologically relevant ligands, basic phenolic neurotransmitters serotonin and dopamine, basic amino acid arginine, and very weakly acidic phenol, in alkaline aqu...
Article
Full-text available
Insulin and insulin-like growth factor 1 (IGF-1) are closely related hormones involved in the regulation of metabolism and growth. They elicit their functions through activation of tyrosine kinase-type receptors: insulin receptors (IR-A and IR-B) and IGF-1 receptor (IGF-1R). Despite similarity in primary and three-dimensional structures, insulin an...
Article
Full-text available
The oligomeric state of the storage form of human insulin in pancreas, which may be affected by several endogenous components of beta cells storage granules such as arginine, is not known. Here, the effect of arginine on insulin oligomerisation is investigated independently by protein crystallography, molecular dynamics simulations and capillary el...
Article
Full-text available
The oligomeric state of the storage form of human insulin in the pancreas, which may be affected by several endogenous components of β-cell storage granules such as arginine, is not known. Here, the effect of arginine on insulin oligomerization is investigated independently by protein crystallography, molecular dynamics simulations, and capillary e...
Article
Full-text available
Insulin-like growth factors 1 and 2 (IGF-1 and -2) are protein hormones involved in normal growth and development, but also in lifespan regulation and cancer. They exert their functions mainly through the IGF-1R receptor, or by binding to the isoform A of insulin receptor (IR-A). The development of IGF-1 and IGF-2 antagonists is of great clinical i...
Article
Full-text available
Non‐natural compounds mimicking the actions of proteins and large peptides can find a plethora of applications in modulating protein‐protein interactions. In this study, we tested the biological properties of three new tripodal and trifunctional scaffolds designed for the solid‐phase synthesis of three different peptides on the same scaffold. Using...
Article
Full-text available
Multi‐orthogonal scaffolds can be useful for the attachment of several different compounds to the same central skeleton. Such compounds can find applications in the development of protein mimics for their potential to mimic several distant epitopes in the protein structure. Based on the structure of our previously published scaffold (Vaněk et al.,...
Preprint
div> The oligomeric state of the storage form of human insulin in pancreas, which may be affected by several endogenous components of beta-cells storage granules such as arginine, is not known. Here, the effect of arginine on insulin oligomerisation is investigated independently by protein crystallography, molecular dynamics simulations and capil...
Article
Full-text available
Human insulin-like growth factor 1 (IGF-1) is a 70-amino acid protein hormone, with key impact on growth, development and lifespan. The physiological and clinical importance of IGF-1 prompted challenging chemical and biological trials towards the development of its analogs as molecular tools for the IGF-1 receptor (IGF1-R) studies, and as new thera...
Article
Full-text available
A significant drawback of the exogenous administration of insulin to diabetics is the non-physiological profile of insulin action resulting in the insufficient suppression of hepatic glucose production, which is the main contributing factor to diabetic hyperglycemia under fasting conditions and the basis of the challenge to restore a more physiolog...
Article
Full-text available
Human insulin is a pivotal protein hormone controlling metabolism, growth and ageing, and whose malfunctioning underlies diabetes, some cancers and neuro-degeneration. Despite its central position in human physiology, the in vivo oligomeric state and conformation of insulin in its storage granules in the pancreas are not known. In contrast, many in...
Article
Full-text available
Human insulin is a pivotal protein hormone controlling metabolism, growth and ageing, and whose malfunctioning underlies diabetes, some cancers and neuro-degeneration. Despite its central position in human physiology, the in vivo oligomeric state and conformation of insulin in its storage granules in the pancreas are not known. In contrast, many in...
Article
Full-text available
The rise of CuI‐catalyzed click chemistry has initiated an increased demand for azido and alkyne derivatives of amino acid as precursors for the synthesis of clicked peptides. However, the use of azido and alkyne amino acids in peptide chemistry is complicated by their high cost. For this reason, we investigated the possibility of the in‐house prep...
Article
We designed a combinatorial library of tri-functional scaffold-derived compounds, which were derivatized with 30 different in-house-made azides. The compounds were proposed to mimic insulin receptor (IR)-binding epitopes in the insulin molecule and bind to and activate this receptor. This work has enabled us to test our synthetic and biological met...
Article
Full-text available
Insulin and insulin-like growth factors I and II are closely related protein hormones. Their distinct evolution has resulted in different yet overlapping biological functions, with insulin becoming a key regulator of metabolism, while IGF-I/II are major growth factors. Insulin and IGFs cross-bind with different affinities to closely related insulin...
Article
Insulin, insulin-like growth factors 1 and 2 (IGF-1/-2), and their receptors (IR, IGF-1R), are the key elements of complex hormonal system that is essential for development and functioning of humans. The C and D domains of IGFs (absent in insulin) are likely playing important roles in the differential binding of IGF-1/-2 to IGF-1R, the isoforms of...
Article
Insulin, insulin-like growth factors 1 and 2 (IGF-1 and -2, respectively), and their receptors (IR and IGF-1R) are the key elements of a complex hormonal system that is essential for the development and functioning of humans. The C and D domains of IGFs (absent in insulin) likely play important roles in the differential binding of IGF-1 and -2 to I...
Article
Full-text available
Insulin is a key hormone of human metabolism with major therapeutic importance for both types of diabetes. New insulin analogues with more physiological profiles and better glycemic control are needed, especially analogues that preferentially bind to the metabolic B-isoform of insulin receptor (IR-B). Here, we aimed to stabilize and modulate the re...
Article
Full-text available
We present a trifunctional scaffold designed for the solid-phase synthesis of trimodal compounds. This scaffold holds two alkyne arms in a free and TIPS-protected form for consecutive CuAAC (copper(I)-catalyzed azide–alkyne cycloaddition), one Fmoc-protected hydrazide arm for reaction with aldehydes, and one carboxylic acid arm with CF2 groups for...
Article
We describe the synthesis of a trifunctional scaffold constructed from a planar core of trimesic acid derivatized with three propargylamine moieties. The scaffold was attached to a solid-phase resin through the carboxylic group of a fluorinated alkyl spacer arm. The orthogonal protection of two of the alkyne groups with triethylsilyl and triisoprop...
Article
Full-text available
The insulin gene mutation c.137G>A (R46Q), which changes an arginine at the B22 position of the mature hormone to glutamine, causes the monogenic diabetes variant maturity-onset diabetes of the young (MODY). In MODY patients, this mutation is heterozygous, and both mutant and wild-type (WT) human insulin are produced simultaneously. However, the pa...
Article
Betaine-homocysteine S-methyltransferase (BHMT) is a zinc-dependent methyltransferase that uses betaine as the methyl donor for the remethylation of homocysteine to form methionine. This reaction supports S-adenosylmethionine biosynthesis, which is required for hundreds of methylation reactions in humans. Herein we report that BHMT is activated by...
Article
Full-text available
The structural characterization of the insulin–insulin receptor (IR) interaction still lacks the conformation of the crucial B21–B30 insulin region, which must be different from that in its storage forms to ensure effective receptor binding. Here, it is shown that insulin analogues modified by natural amino acids at the TyrB26 site can represent an...
Article
The N-terminus of the B-chain of insulin may adopt two alternative conformations designated as the T- and R-states. Despite the recent structural insight into insulin:insulin receptor (IR) complexes, the physiological relevance of the T/R transition is still unclear. Hence this study focused on the rational design, synthesis and characterization of...
Article
Full-text available
Until recently, despite decades of intensive research, the exact mode of interaction of insulin with its membrane receptor remained elusive. However, recent advances achieved with insulin analogues and crystallographic studies with the insulin receptor provided a first insight into the interaction of insulin with its primary binding site on the ins...
Article
The chiral shift reagents Sm-(R)-pdta and Sm-(S)-pdta, which are based on (R)- or (S)-1,2-diaminopropane-N,N,N',N'-tetraacetic acid were synthesized from easily accessible compounds in three simple steps, which makes the method suitable for laboratory-scale production. In addition, a new and efficient method for the preparation of pure anhydrous (R...
Article
Betaine-homocysteine S-methyltransferase (BHMT) is an important zinc-dependent methyltransferase that uses betaine as the methyl donor for the remethylation of homocysteine to form methionine. In the liver, BHMT performs to half of the homocysteine remethylation. In this study, we systematically investigated the tolerance of the enzyme for modifica...
Article
Full-text available
Despite the recent first insight into the insulin-insulin receptor complex, the structural role of the C-terminus of the B-chain of insulin in this assembly remains unresolved. Previous studies have suggested that this part of insulin must rearrange to reveal amino acids crucial for interaction with the receptor. The role of the invariant PheB24, o...
Article
Full-text available
Insulin receptor signalling has a central role in mammalian biology, regulating cellular metabolism, growth, division, differentiation and survival. Insulin resistance contributes to the pathogenesis of type 2 diabetes mellitus and the onset of Alzheimer's disease; aberrant signalling occurs in diverse cancers, exacerbated by cross-talk with the ho...
Article
We optimized and validated a rapid and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the quantification of six metabolites of homocysteine metabolism: homocysteine, methionine, cysteine, S-adenosylmethionine, S-adenosylhomocysteine and betaine. The detection limits for these metabolites were in the nanomolar range,...
Article
Betaine-homocysteine S-methyltransferase 2 (BHMT-2) catalyzes the transfer of a methyl group from S-methylmethionine to l-homocysteine, yielding two molecules of l-methionine. It is one of three homocysteine methyltransferases in mammals, but its overall contribution to homocysteine remethylation and sulfur amino acid homeostasis is not known. More...
Article
Full-text available
The insulin receptor isoform A (IR-A) binds both insulin and insulin-like growth factor (IGF)-II, although the affinity for IGF-II is 3-10-fold lower than insulin depending on a cell and tissue context. Notably, in mouse embryonic fibroblasts lacking the IGF-IR and expressing solely the IR-A (R-/IR-A), IGF-II is a more potent mitogen than insulin....