| Sažetak | Proteini su osnovne funkcionalne molekule u živim organizmima te obavljaju bitne zadaće u svim biološkim procesima. Biološke funkcije koje obavljaju su npr. enzimska kataliza, prijenos i pohrana kisika, imunološka zaštita, mehanička čvrstoća, hormonska regulacija, stvaranje i provođenje živčanih impulsa, pa i sama kontrola genske ekspresije. Proteini su građeni od 20 standardnih aminokiselina koje možemo unositi hranom ili sami proizvoditi. Biosinteza proteina se naziva translacijom gdje se informacija s nukleinske kiseline (mRNA) prevodi u slijed aminokiselina koje prenose transfer-RNA (tRNA). Zbog komplemetarnosti baza kodona i antikodona nastaje niz aminokiselina koje se povezuju peptidnom vezom. Svaka aminokiselina se aktivira i povezuje s tRNA zahvaljujući enzimu aminoacil-tRNA-sintetazi. Postoji najmanje jedna aminoacil-tRNA-sintetaza i jedna tRNA za svaku aminokiselinu. Strukturna organizacija proteina podijeljena je u 4 razine: Primarna struktura predstavlja slijed aminokiselina povezanih peptidnom vezom. Priroda bočnih ogranaka aminokiselina određuje prostornu strukturu proteina. Sekundarna struktura je početak trodimenzionalnosti proteina. Sekundarni strukturni elementi su α-uzvojnice, β-listovi i okreti nastali kao posljedica torzijskih kutova i djelovanja vodikovih veza između amino i karboksilnih skupina aminokiselinskih ostataka u polipeptidnom lancu. Tercijarna struktura je prostorna organizacija proteina. Termodinamski najpovoljnija 3D-struktura proteina ovisi o slijedu aminokiselinskih ostataka u proteinu. Funkcija svakog proteina ovisi o prostornoj konformaciji proteina. Kvaterna struktura se odnosi na proteine koji sadrže više polipeptidnih lanaca kao što je npr. hemoglobin 25 Jako je važno održati svaki stupanj organizacije proteina ispravnim ali su oni jako osjetljivi na fizikalne i kemijske promjene u svojoj okolini. Promjena genetičkog materijala kao posljedicu može imati ugradnju pogrešne aminokiseline u polipeptidni lanac. Iz nativnog stanja protein denaturacijom mijenja svoju sekundarnu i tercijarnu strukturu, ali ne i primarnu. Postoje različita sredstva za denaturaciju koja kidaju nekovalentne i disulfidne veze pri čemu se protein razmata, a kao takav nema više svoju biološku funkciju. Najčešća denaturacijska sredstva su visoka i niska temperatura, alkohol, deterdženti, jake lužine i kiseline, oksidacijska i redukcijska sredstva i teški metali. Glavne posljedice denaturacije su smanjena topljivost proteina, porast proteolize, gubitak biološke funkcije i stvaranje proteinskih agregata. Sustav za razgradnju proteina koji mogu biti pogrješno smotani ili denaturirani je proteinski kompleks ubikvitin-proteosom. Koristeći tri enzima ubikvitin se veže izopeptidnom vezom na krajnju amino skupinu lizinskog ostatka nepravilnog proteina. Za stvaranje izopeptidne veze potrebna je energija koja se dobije hidrolizom molekule ATP-a. Proteosom je veliki proteinski kompleks koji se sastoji od katalitičke 20S i regulatorne 19S jedinice i služe za razgradnju ubikvitiniranih proteina. Proteinski agregati mogu nastati denaturacijom, nefunkcioniranjem šaperona, ali i starenjem stanica, spriječenom autofagijom, oksidativnim stresom, mutagenim sredstvima, poremećajem u radu proteosoma i povećanom ekspresijom proteina. Nakupine nemaju funkciju u stanicama, smetaju drugim proteinima da obavljaju svoje zadaće i najčešći su uzrok nastanka neurodegenerativnih bolesti kao što su Alzheimerova, Parkinsonova i Huntingtonova bolest, amiotrofična lateralna skleroza i bolesti uzrokovane prionima kao na primjer goveđi spongiformni encefalitis (kravlje ludilo). Niti jedna od ovih bolesti nije izlječiva, terapija je uglavnom simptomatska i individualna. U novije vrijeme se koristi genska terapija, terapija monoklonskim antitijelima i matičnim stanicama sve s ciljem pronalaska lijeka oboljelima od ovih teških bolesti. |
| Sažetak (engleski) | Proteins are the basic functional molecules in living organisms and perform essential tasks in all biological processes. Biological functions performed by proteins, for example, are enzymatic catalysis, transfer and storage of oxygen, immune protection, mechanical strength, hormonal regulation, creation and implementation of nerve impulses, and even the control of gene expression. Proteins are made up of 20 standard amino acids that can be ingested in form of food or produced by biosynthesis. The biosynthesis of proteins is called translation, where by the information derived from messenger RNA (mRNA) is converted into a sequence of amino acids that are transmitted via transfer RNA (tRNA). Due to the complementarity of the codon and the anticodon, a series of amino acids that are linked by peptide bonds. Each amino acid is activated and connected to the tRNA due to the enzyme - aminoacyl tRNA synthetase. There is at least one aminoacyl - tRNA synthetase and tRNA for each amino acid. The structural organization of proteins is divided into four levels: • The primary structure represents the sequence of amino acid residues linked by peptide bonds. The nature of the side chains of the amino acids determines the spatial structure of the protein. • The secondary structure is the beginning of protein assembly into three-dimensional structure. The secondary structural elements are the α - helix, β - sheets and turns resulting from torsion angles and the effect of hydrogen bonds between the amino and carboxyl groups of amino acids in the polypeptide chain. • The tertiary structure is the spatial organization of protein. The optimal thermodynamically favorable 3D - structure of a proteins depend on the sequence of amino acid residues in the protein. The function of each protein is dependent on the spatial conformation of the protein. • The quaternary structure refers to proteins that have multiple polypeptide chains such as hemoglobin. 27 It is very important to maintain each level of protein organization correct, hovwever proteins are very sensitive to physical and chemical changes in their environment. Any change in the genetic material may cause the incorporation of a noncognate amino acid into the polypeptide chain. Due to denaturation, the protein changes its secondary and tertiary structure, but not the primary structure. There are various types of denaturation agents that cleave non-covalent and disulfide bonds cousing the protein to unwind, and looses its biological function. The most common denaturing agents are high and low temperature, alcohol, detergents, strong alkali and acids, oxidizing and reducing agents and heavy metals. The main consequences of denaturation are reduced solubility of proteins, increase proteolysis, loss of biological function and formation of protein aggregates. The system, involved in protein degradation is ubiquitin - proteosome complex. Ubiquitin uses three enzy mes to make an isopeptide bond with the amino group of a lysine residue in the target protein. Formation of an isopeptide connection requires energy, which is obtained by hydrolysis of ATP molecule. The proteasome is a large protein complex made of a catalytic 20S and 19S regulatory unit, and serves for the degradation of proteins labelled by ubiquitin. Protein aggregates can be formed by denaturation, non-functional chaperones or aging cells, prevented autophagy, oxidative stress, mutagenic agents,a dysfunctional proteasome and overexpression of proteins. Protein clusters have no function in the cell, interfere with other proteins and prevent them from performing their tasks, and they are the most common cause of neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's disease, amyotrophic lateral sclerosis and prion-mediated diseases such as bovine spongiform encephalitis (mad cow disease). None of these diseases are curable, treatment is mostly symptomatic and individual. More recently gene therapy, monoclonal antibody therapy and stem cells have been used, with the aim to cure those suffering from these serious diseases. |
