Protein metabolism denotes the variousbiochemical processes responsible for thesynthesis of proteins andamino acids (anabolism), and the breakdown ofproteins bycatabolism.

The steps ofprotein synthesis includetranscription,translation, and post translational modifications. During transcription,RNA polymerase transcribes a coding region of theDNA in a cell producing a sequence of RNA, specificallymessenger RNA (mRNA). This mRNA sequence contains codons: 3 nucleotide long segments that code for a specific amino acid. Ribosomes translate the codons to their respective amino acids.^[1] In humans,non-essential amino acids are synthesized from intermediates in major metabolic pathways such as theCitric Acid Cycle.^[2]Essential amino acids must be consumed and are made in other organisms. The amino acids are joined by peptide bonds making a polypeptide chain. This polypeptide chain then goes through post translational modifications and is sometimes joined with other polypeptide chains to form a fully functional protein.

Dietary proteins are first broken down to individual amino acids by various enzymes andhydrochloric acid present in the gastrointestinal tract. These amino acids are absorbed into the bloodstream to be transported to the liver and onward to the rest of the body. Absorbed amino acids are typically used to create functional proteins, but may also be used to create energy.^[3] They can also be converted into glucose.^[4] This glucose can then be converted totriglycerides and stored in fat cells.^[5]

Proteins can be broken down by enzymes known aspeptidases or can break down as a result ofdenaturation. Proteins can denature in environmental conditions the protein is not made for.^[6]

Protein anabolism is the process by which proteins are formed from amino acids. It relies on five processes:amino acid synthesis,transcription,translation,post translational modifications, andprotein folding. Proteins are made from amino acids. In humans, some amino acids can besynthesized using already existing intermediates. These amino acids are known as non-essential amino acids.Essential amino acids require intermediates not present in the human body. These intermediates must be ingested, mostly from eating other organisms.^[6]  

Intranscription,RNA polymerase reads a DNA strand and produces anmRNA strand that can be further translated. In order to initiate transcription, the DNA segment that is to be transcribed must be accessible (i.e. it cannot be tightly packed). Once the DNA segment is accessible, the RNA polymerase can begin to transcribe the coding DNA strand by pairing RNA nucleotides to the template DNA strand. During the initial transcription phase, the RNA polymerase searches for apromoter region on the DNA template strand. Once the RNA polymerase binds to this region, it begins to “read” the template DNA strand in the 3’ to 5’ direction.^[8] RNA polymerase attaches RNA bases complementary to the template DNA strand (Uracil will be used instead ofThymine). The newnucleotide bases are bonded to each other covalently.^[9] The new bases eventually dissociate from the DNA bases but stay linked to each other, forming a new mRNA strand. This mRNA strand is synthesized in the 5’ to 3’ direction.^[10] Once the RNA reaches aterminator sequence, it dissociates from the DNA template strand and terminates the mRNA sequence as well.

Transcription is regulated in the cell via transcription factors. Transcription factors are proteins that bind to regulatory sequences in the DNA strand such as promoter regions or operator regions. Proteins bound to these regions can either directly halt or allow RNA polymerase to read the DNA strand or can signal other proteins to halt or allow RNA polymerase reading.^[11]

Duringtranslation,ribosomes convert a sequence of mRNA (messenger RNA) to an amino acid sequence. Each 3-base-pair-long segment of mRNA is acodon which corresponds to oneamino acid or stop signal.^[12] Amino acids can have multiple codons that correspond to them. Ribosomes do not directly attach amino acids to mRNA codons. They must utilizetRNAs (transfer RNAs) as well. Transfer RNAs can bind to amino acids and contain an anticodon which can hydrogen bind to an mRNA codon.^[13] The process of bind an amino acid to a tRNA is known as tRNA charging. Here, the enzymeaminoacyl-tRNA-synthetase catalyzes two reactions. In the first one, it attaches an AMP molecule (cleaved from ATP) to the amino acid. The second reaction cleaves the aminoacyl-AMP producing the energy to join the amino acid to the tRNA molecule.^[14]

Ribosomes have twosubunits, one large and one small. These subunits surround the mRNA strand. The larger subunit contains three binding sites: A (aminoacyl), P (peptidyl), and E (exit). After translational initiation (which is different inprokaryotes andeukaryotes), the ribosome enters the elongation period which follows a repetitive cycle. First a tRNA with the correct amino acid enters the A site. The ribosome transfers the peptide from the tRNA in the P site to the new amino acid on the tRNA in the A site. The tRNA from the P site will be shifted into the E site where it will be ejected. This continually occurs until the ribosome reaches astop codon or receives a signal to stop.^[13] Apeptide bond forms between the amino acid attached to the tRNA in the P site and the amino acid attached to a tRNA in the A site. The formation of a peptide bond requires an input of energy. The two reacting molecules are the alpha amino group of one amino acid and the alpha carboxyl group of the other amino acids. A by-product of this bond formation is the release of water (the amino group donates a proton while the carboxyl group donates a hydroxyl).^[2]

Translation can bedownregulated bymiRNAs (microRNAs). These RNA strands can cleave mRNA strands they arecomplementary to and will thus stop translation.^[15] Translation can also be regulated via helper proteins. For example, a protein called eukaryotic initiation factor-2 (eIF-2) can bind to the smaller subunit of the ribosome, starting translation. When elF-2 isphosphorylated, it cannot bind to the ribosome and translation is halted.^[16]

Once thepeptide chain is synthesized, it still must be modified.Post-translational modifications can occur before protein folding or after. Common biological methods of modifying peptide chains after translation includemethylation,phosphorylation, anddisulfide bond formation. Methylation often occurs toarginine orlysine and involves adding amethyl group to anitrogen (replacing ahydrogen). TheR groups on these amino acids can bemethylated multiple times as long as the bonds to nitrogen does not exceed 4. Methylation reduces the ability of these amino acids to form hydrogen bonds so arginine and lysine that are methylated have different properties than their standard counterparts.Phosphorylation often occurs toserine,threonine, andtyrosine and involves replacing a hydrogen on thealcohol group at the terminus of the R group with aphosphate group. This adds a negative charge on the R groups and will thus change how the amino acids behave in comparison to their standard counterparts.Disulfide bond formation is the creation of disulfide bridges (covalent bonds) between twocysteine amino acids in a chain which adds stability to the folded structure.^[17]

A polypeptide chain in the cell does not have to stay linear; it can become branched or fold in on itself. Polypeptide chains fold in a particular manner depending on the solution they are in. The fact that all amino acids contain R groups with different properties is the main reason proteins fold.

• In ahydrophilic environment such ascytosol, thehydrophobic amino acids will concentrate at the core of the protein, while the hydrophilic amino acids will be on the exterior. This isentropically favorable since water molecules can move much more freely around hydrophilic amino acids than hydrophobic amino acids.
• In a hydrophobic environment, the hydrophilic amino acids will concentrate at the core of the protein, while the hydrophobic amino acids will be on the exterior. Since the new interactions between the hydrophilic amino acids are stronger than hydrophobic-hydrophilic interactions, this isenthalpically favorable.^[18]

Once a polypeptide chain is fully folded, it is called a protein. Often many subunits will combine to make a fully functional protein although physiological proteins do exist that contain only one polypeptide chain. Proteins may also incorporate other molecules such as theheme group inhemoglobin, a protein responsible for carrying oxygen in the blood.^[19]

Protein catabolism is the process by whichproteins are broken down to theiramino acids. This is also calledproteolysis and can be followed by furtheramino acid degradation.

Originally thought to only disruptenzymatic reactions,proteases (also known aspeptidases) actually help with catabolizing proteins through cleavage and creating new proteins that were not present before. Proteases also help to regulatemetabolic pathways. One way they do this is to cleave enzymes in pathways that do not need to be running (i.e.gluconeogenesis when bloodglucose concentrations are high). This helps to conserve as much energy as possible and to avoidfutile cycles. Futile cycles occur when the catabolic and anabolic pathways are both in effect at the same time and rate for the same reaction. Since the intermediates being created are consumed, the body makes no net gain. Energy is lost through futile cycles. Proteases prevent this cycle from occurring by altering the rate of one of the pathways, or by cleaving a key enzyme, they can stop one of the pathways. Proteases are also nonspecific when binding tosubstrate, allowing for great amounts of diversity inside the cells and other proteins, as they can be cleaved much easier in an energy efficient manner.^[20]

Because many proteases are nonspecific, they are highly regulated in the cell. Without regulation, proteases will destroy many proteins which are essential to physiological processes. One way the body regulates proteases is throughprotease inhibitors. Protease inhibitors can be other proteins, small peptides, or molecules. There are two types of protease inhibitors: reversible and irreversible. Reversible protease inhibitors formnon-covalent interactions with the protease limiting its functionality. They can becompetitive inhibitors,uncompetitive inhibitors, andnoncompetitive inhibitors. Competitive inhibitors compete with the peptide to bind to the protease active site. Uncompetitive inhibitors bind to the protease while the peptide is bound but do not let the protease cleave the peptide bond. Noncompetitive inhibitors can do both. Irreversible protease inhibitorscovalently modify the active site of the protease so it cannot cleave peptides.^[21]

Exopeptidases are enzymes that can cleave the end of an amino acid side chain mostly through the addition of water.^[6] Exopeptidase enzymes exist in the small intestine. These enzymes have two classes:aminopeptidases are a brush border enzyme andcarboxypeptidases which is from the pancreas. Aminopeptidases are enzymes that remove amino acids from theamino terminus of protein. They are present in all lifeforms and are crucial for survival since they do many cellular tasks in order to maintain stability. This form of peptidase is a zinc metalloenzyme and it is inhibited by thetransition state analog. This analog is similar to the actualtransition state, so it can make the enzyme bind to it instead of the actual transition state, thus preventing substrate binding and decreasing reaction rates.^[22] Carboxypeptidases cleave at thecarboxyl end of the protein. While they cancatabolize proteins, they are more often used inpost-transcriptional modifications.^[23]

Endopeptidases are enzymes that add water to an internalpeptide bond in apeptide chain and break that bond.^[6] Three common endopeptidases that come from the pancreas arepepsin,trypsin, andchymotrypsin. Chymotrypsin performs ahydrolysis reaction that cleaves afteraromatic residues. The main amino acids involved areserine,histidine, andaspartic acid. They all play a role in cleaving the peptide bond. These three amino acids are known as thecatalytic triad which means that these three must all be present in order to properly function.^[6] Trypsin cleaves after long positively charged residues and has a negatively charged binding pocket at theactive site. Both are produced aszymogens, meaning they are initially found in their inactive state and after cleavage though a hydrolysis reaction, they becomes activated.^[2]Non-covalent interactions such ashydrogen bonding between the peptide backbone and the catalytic triad help increase reaction rates, allowing these peptidases to cleave many peptides efficiently.^[6]

Cellular proteins are held in a relatively constant pH in order to prevent changes in the protonation state of amino acids.^[24] If thepH drops, some amino acids in the polypeptide chain can becomeprotonated if thepka of theirR groups is higher than the new pH. Protonation can change the charge these R groups have. If the pH raises, some amino acids in the chain can becomedeprotonated (if the pka of the R group is lower than the new pH). This also changes the R group charge. Since many amino acids interact with other amino acids based onelectrostatic attraction, changing the charge can break these interactions. The loss of these interactions alters theproteins structure, but most importantly it alters the proteins function, which can be beneficial or detrimental. A significant change in pH may even disrupt many interactions the amino acids make anddenature (unfold) the protein.^[24]

As thetemperature in the environment increases, molecules move faster.Hydrogen bonds andhydrophobic interactions are important stabilizing forces in proteins. If the temperature rises and molecules containing these interactions are moving too fast, the interactions become compromised or even break. At high temperatures, these interactions cannot form, and a functional protein isdenatured.^[25] However, it relies on two factors; the type of protein used and the amount of heat applied. The amount of heat applied determines whether this change in protein is permanent or if it can be transformed back to its original form.^[26]

• Protein metabolism

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