Metallopeptide

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Metallopeptides (also called metal-peptides or metal peptide complexes) are peptides that contain one or more metal ions in their structure. This specific type of peptide are, just like metalloproteins, metallofoldamers. And very similar to metalloproteins, metallopeptide's functionality is attibuted through the contained metal ion cofactor. These short structured peptides are often employed to develop mimics of metalloproteins and systems similar to artificial metalloenzymes.

Contents

A multitude of naturally occurring peptides display biological and chemical activities when bound to various metal ions. Where different metal ion cofactor can lead to different reactivity and even different folding and physical characteristics (e.g. solubility or stability) of the structure. Synthetic equivalents of such peptides are engineered to bind metal ions and display a variety of physical, chemical, and biological reactivity and characteristics.

Examples

In the last 40 years, there has been a significant amount of research on metal binding peptides and their characteristics, structures, and chemical reactivities. [1]

Vincent L. Pecoraro and his group investigate the interaction of peptides with heavy metals in the body; Katherine Franz leads a group studying Cu-binding peptides; Angela Lombardi and her unit focus on the development of artificial metalloenzymes and similar peptide systems, and the group of Peter Faller focuses on redox reactivity of Cu-peptides. [2] [3]

Natural

Natural metallopeptides with antibiotic, antimicrobial and anticancer properties have been of particular interest to the scientific community (e.g. the divalent bacitracin, histatin and Fe/Cu-bleomycin). [4] [5] At the same time there is an increasing attention to the role of metalloppeptides in disease development. For example, metallochemical interactions in brain tissue can contribute to neurodegenerative conditions due to the naturally high concentration of metal ions in the brain. Hence the metallochemical reactions occurring outside the physiologically healthy concentrations, can contribute to the development of diseases such as Alzheimer's disease. The condition is related to the β-amyloid metallopeptides. [6] Another example are infectious prion polypeptides and specific isoforms of prion protein which contribute to disease transmission and development. [7]

Artificial

De novo designed peptides which self-assemble in the presence of copper (Cu), forming supramolecular assemblies were presented by Korendovych et al. [8] Additionally there are examples of metallopeptides that are, at least partially, composed of non-natural amino acids with possible applications in drug discovery and biomaterials. [9]

Metal coordination

Being a type of molecules that are often only activated for biological and chemical function following metal-binding, the specific coordination of metal ions imposes certain restrictions and requirements onto metallopeptides. Usually metal cofactors are coordinated by nitrogen, oxygen or sulfur centers belonging to amino acid residues of the peptide. These donor groups can be introduced by histidine (or the corresponding imidazole), cysteine (thiolate group), as well as carboxylate substituents (e.g by aspartate) but are not limited to these. The other amino acid residues, including non-natural amino acids and the peptide backbone have been shown to bind metal centers and provide donor groups. The research on metal-binding of peptides ranges from coordination of biometals (such as Calcium, Magnesium, Manganese, Zinc, Sodium, Potassium, and Iron) to heavy metals (such as Arsenic, Mercury, and Cadmium). [10] [11]

Synthesis and analysis

Biosynthesis

Peptides are synthesized in living organisms inside the cell analogously to proteins.

Chemical synthesis

Solid phase peptide synthesis (SPPS) is a well-established method for producing synthetic peptides. SPPS enables the building of a peptide chain by sequential interactions of amino acid derivatives.

Analysis

The interaction between metal ions and peptides are typically studied in solution using spectroscopic or electrochemical methods. Amongst which are circular dichroism (CD), nuclear magnetic resonance (NMR) spectroscopy, cyclic voltammetry, and mass spectrometry (MS). [1]

See also

Related Research Articles

<span class="mw-page-title-main">Histidine</span> Chemical compound

Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated –NH3+ form under biological conditions), a carboxylic acid group (which is in the deprotonated –COO− form under biological conditions), and an imidazole side chain (which is partially protonated), classifying it as a positively charged amino acid at physiological pH. Initially thought essential only for infants, it has now been shown in longer-term studies to be essential for adults also. It is encoded by the codons CAU and CAC.

Chelation is a type of bonding of ions and the molecules to metal ions. It involves the formation or presence of two or more separate coordinate bonds between a polydentate ligand and a single central metal atom. These ligands are called chelants, chelators, chelating agents, or sequestering agents. They are usually organic compounds, but this is not a necessity.

<span class="mw-page-title-main">Metalloprotein</span> Protein that contains a metal ion cofactor

Metalloprotein is a generic term for a protein that contains a metal ion cofactor. A large proportion of all proteins are part of this category. For instance, at least 1000 human proteins contain zinc-binding protein domains although there may be up to 3000 human zinc metalloproteins.

<span class="mw-page-title-main">Metallothionein</span> Family of proteins

Metallothionein (MT) is a family of cysteine-rich, low molecular weight proteins. They are localized to the membrane of the Golgi apparatus. MTs have the capacity to bind both physiological and xenobiotic heavy metals through the thiol group of its cysteine residues, which represent nearly 30% of its constituent amino acid residues.

<span class="mw-page-title-main">Plastocyanin</span>

Plastocyanin is a copper-containing protein that mediates electron-transfer. It is found in a variety of plants, where it participates in photosynthesis. The protein is a prototype of the blue copper proteins, a family of intensely blue-colored metalloproteins. Specifically, it falls into the group of small type I blue copper proteins called "cupredoxins".

<span class="mw-page-title-main">ATP7A</span> Protein-coding gene in humans

ATP7A, also known as Menkes' protein (MNK), is a copper-transporting P-type ATPase which uses the energy arising from ATP hydrolysis to transport Cu(I) across cell membranes. The ATP7A protein is a transmembrane protein and is expressed in the intestine and all tissues except liver. In the intestine, ATP7A regulates Cu(I) absorption in the human body by transporting Cu(I) from the small intestine into the blood. In other tissues, ATP7A shuttles between the Golgi apparatus and the cell membrane to maintain proper Cu(I) concentrations in the cell and provides certain enzymes with Cu(I). The X-linked, inherited, lethal genetic disorder of the ATP7A gene causes Menkes disease, a copper deficiency resulting in early childhood death.

Catechol oxidase is a copper oxidase that contains a type 3 di-copper cofactor and catalyzes the oxidation of ortho-diphenols into ortho-quinones coupled with the reduction of molecular oxygen to water. It is present in a variety of species of plants and fungi including Ipomoea batatas and Camellia sinensis. Metalloenzymes with type 3 copper centers are characterized by their ability to reversibly bind dioxygen at ambient conditions. In plants, catechol oxidase plays a key role in enzymatic browning by catalyzing the oxidation of catechol to o-quinone in the presence of oxygen, which can rapidly polymerize to form the melanin that grants damaged fruits their dark brown coloration.

Nitrite reductase refers to any of several classes of enzymes that catalyze the reduction of nitrite. There are two classes of NIR's. A multi haem enzyme reduces NO2− to a variety of products. Copper containing enzymes carry out a single electron transfer to produce nitric oxide.

<span class="mw-page-title-main">Aminopeptidase</span> Class of enzymes

Aminopeptidases are enzymes that catalyze the cleavage of amino acids from the N-terminus (beginning), of proteins or peptides. They are found in many organisms; in the cell, they are found in many organelles, in the cytosol, and as membrane proteins. Aminopeptidases are used in essential cellular functions, and are often zinc metalloenzymes, containing a zinc cofactor.

<span class="mw-page-title-main">Biometal (biology)</span> Metal in biology, biochemistry, and medicine

Biometals are metals normally present, in small but important and measurable amounts, in biology, biochemistry, and medicine. The metals copper, zinc, iron, and manganese are examples of metals that are essential for the normal functioning of most plants and the bodies of most animals, such as the human body. A few are present in relatively larger amounts, whereas most others are trace metals, present in smaller but important amounts. Approximately 2/3 of the existing periodic table is composed of metals with varying properties, accounting for the diverse ways in which metals have been utilized in nature and medicine.

<span class="mw-page-title-main">Enzyme catalysis</span> Catalysis of chemical reactions by enzymes

Enzyme catalysis is the increase in the rate of a process by a biological molecule, an "enzyme". Most enzymes are proteins, and most such processes are chemical reactions. Within the enzyme, generally catalysis occurs at a localized site, called the active site.

QPNC-PAGE, or QuantitativePreparativeNativeContinuousPolyacrylamideGel Electrophoresis, is a bioanalytical, one-dimensional, high-resolution and high-precision electrophoresis technique applied in biochemistry and bioinorganic chemistry to separate proteins quantitatively by isoelectric point and by continuous elution from a gel column.

<span class="mw-page-title-main">ATOX1</span> Protein-coding gene in the species Homo sapiens

ATOX1 is a copper metallochaperone protein that is encoded by the ATOX1 gene in humans. In mammals, ATOX1 plays a key role in copper homeostasis as it delivers copper from the cytosol to transporters ATP7A and ATP7B. Homologous proteins are found in a wide variety of eukaryotes, including Saccharomyces cerevisiae as ATX1, and all contain a conserved metal binding domain.

Histatins are histidine-rich (cationic) antimicrobial proteins found in saliva. Histatin's involvement in antimicrobial activities makes histatin part of the innate immune system.

Amy C. Rosenzweig is a professor of Chemistry and Molecular Biosciences at Northwestern University. She was born in 1967 in Pittsburgh, Pennsylvania. Her current research interests include structural biology and bioinorganic chemistry, metal uptake and transport, oxygen activation by metalloenzymes, and characterization of membrane protein. For her work, she has been recognized by a number of national and international awards, including the MacArthur "Genius" Award in 2003.

Metallochaperones are a distinct class of molecular chaperones that facilitate the intracellular transport of metal ions to different metalloproteins, e.g. metalloenzymes, in cells through specific protein-protein interactions. In this way, for example, the proteins ensure that the correct metal ion cofactor is acquired by its corresponding metalloenzyme. Metallochaperones are essential to the proper functioning of cells, playing a vital role in a large number of biological processes including, for example, respiration, photosynthesis, neurotransmission, and protein folding.

<span class="mw-page-title-main">Metal-binding protein</span> Proteins or protein domains that chelate a metal ion

Metal-binding proteins are proteins or protein domains that chelate a metal ion.

An Artificial Metalloenzyme (ArM) is a designer metalloprotein, not found in nature, which can catalyze desired chemical reactions. Despite fitting into classical enzyme categories, ArMs also have potential in new-to-nature chemical reactivity like catalysing Suzuki coupling, Metathesis etc., which were never reported among natural enzymatic reactions.

Katherine J. Franz is the chair of the department of chemistry at Duke University. She studies metal ion coordination in biological systems and looks to use the insight to manage species such as copper and iron. Franz was awarded the American Chemical Society Award for Encouraging Women into Careers in the Chemical Sciences.

<span class="mw-page-title-main">Bibudhendra Sarkar</span>

Bibudhendra (Amu) Sarkar is a Canadian biochemist best known for his research on copper-histidine in human blood, leading to the first treatments for Menkes disease. He served as head of the Division of Biochemistry Research at the Sick Kids Research Institute in Toronto from 1990-2002, where he established the Department of Structural Biology Research in 1990.

References

  1. 1 2 Murariu M, Dragan ES, Drochioiu G (June 2010). "Model peptide-based system used for the investigation of metal ions binding to histidine-containing polypeptides". Biopolymers. 93 (6): 497–508. doi:10.1002/bip.21385. PMID   20091672.
  2. ↑ DeGrado WF, Summa CM, Pavone V, Nastri F, Lombardi A (1999-06-07). "De novo design and structural characterization of proteins and metalloproteins". Annual Review of Biochemistry. 68 (1): 779–819. doi:10.1146/annurev.biochem.68.1.779. PMID   10872466.
  3. ↑ Okafor M, Champomier O, Raibaut L, Ozkan S, El Kholti N, Ory S, et al. (2024-04-05). "Restoring cellular copper homeostasis in Alzheimer disease: a novel peptide shuttle is internalized by an ATP-dependent endocytosis pathway involving Rab5- and Rab14-endosomes". Frontiers in Molecular Biosciences. 11: 1355963. doi: 10.3389/fmolb.2024.1355963 . PMC   11026709 . PMID   38645276.
  4. ↑ Ming LJ (2010-09-25). "Metallopeptides — from Drug Discovery to Catalysis". Journal of the Chinese Chemical Society. 57 (3A): 285–299. doi:10.1002/jccs.201000043. ISSN   0009-4536.
  5. ↑ Conklin SE, Bridgman EC, Su Q, Riggs-Gelasco P, Haas KL, Franz KJ (August 2017). "Specific Histidine Residues Confer Histatin Peptides with Copper-Dependent Activity against Candida albicans". Biochemistry. 56 (32): 4244–4255. doi:10.1021/acs.biochem.7b00348. PMC   5937946 . PMID   28763199.
  6. ↑ Barnham KJ, McKinstry WJ, Multhaup G, Galatis D, Morton CJ, Curtain CC, et al. (May 2003). "Structure of the Alzheimer's disease amyloid precursor protein copper binding domain. A regulator of neuronal copper homeostasis". The Journal of Biological Chemistry. 278 (19): 17401–17407. doi: 10.1074/jbc.M300629200 . PMID   12611883.
  7. ↑ Daus ML (January 2016). "Disease Transmission by Misfolded Prion-Protein Isoforms, Prion-Like Amyloids, Functional Amyloids and the Central Dogma". Biology. 5 (1): 2. doi: 10.3390/biology5010002 . PMC   4810159 . PMID   26742083.
  8. ↑ Makhlynets OV, Gosavi PM, Korendovych IV (July 2016). "Short Self-Assembling Peptides Are Able to Bind to Copper and Activate Oxygen". Angewandte Chemie. 55 (31): 9017–9020. doi:10.1002/anie.201602480. PMC   5064842 . PMID   27276534.
  9. ↑ Lewis JC (April 2015). "Metallopeptide catalysts and artificial metalloenzymes containing unnatural amino acids". Current Opinion in Chemical Biology. Biocatalysis and biotransformation • Bioinorganic chemistry. 25: 27–35. doi:10.1016/j.cbpa.2014.12.016. PMC   4380757 . PMID   25545848.
  10. ↑ Rulísek L, Vondrásek J (September 1998). "Coordination geometries of selected transition metal ions (Co2+, Ni2+, Cu2+, Zn2+, Cd2+, and Hg2+) in metalloproteins". Journal of Inorganic Biochemistry. 71 (3–4): 115–127. doi:10.1016/S0162-0134(98)10042-9. PMID   9833317.
  11. ↑ Hausinger RP (December 2019). "New metal cofactors and recent metallocofactor insights". Current Opinion in Structural Biology. Catalysis and Regulation ● Protein Nucleic Interactions. 59: 1–8. doi:10.1016/j.sbi.2018.12.008. PMID   30711735.
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