Biochemitsry - N2 Metabolism And Plasma Proteins Flashcards
Step 1 of Protein Translation
Initiation: during initiation, the components of the translational apparatus come together with an mRNA and a tRNA carrying the first amino acid (AA1) binds to the start codon (AUG)
Step 2 of Protein Translation
Elongation: During elongation, AAs are brought to the mRNA by tRNAs and are added one by one to a growing polypeptide chain
Step 3 of Protein Translation
Termination: during termination, a stop codon in the mRNA is recognized by a protein release factor, and the translational apparatus comes apart, releasing a completed polypeptide.
Primary protein structure
A sequence of amino acids
Secondary protein structure
H-binding of the peptide backbone causes the AAs to fold into a repeating pattern
Tertiary protein sturcture
3D folding pattern of a protein due to side chain interactions
Quaternary protein structure
Protein consisting of more than 1 AA chain
General principles of protein modification, transport, and secretion (5)
- Secretory pathway
- Post-translational modification
- Packaging
- Vesicular transport: cellular destination, extracellular destination (signaling peptides)
- Exocytosis: a form of secretion, best understood mechanism
Steps of protein modification, transport, and secretion (5)
1A: RER synthesizes proteins and packages them in vesicles
1B: SER synthesizes lipids and has various other functions
- Transport vesicles takes proteins and lipids to the Golgi apparatus
- Golgi modifies the lipids and proteins from the ER; sorts and packages them back into secretory vesicles
- Secretory vesicles travel to the plasma membrane, fuse, and expel their contents extracellularly
- Simultaneously, material entering the cell via endocytosis fuse with a lysosome that contains digestive enzymes that break down contents for recycling
Plasma proteins are composed of:
Protein and hetero-oligosaccharide chains that are short, branched, w/ or w/o negative charge, and have no repeating disaccharide units
Plasma proteins contain:
N-terminal signal sequence that targets the growing polypeptide chain to the ER for N-glycosylation and then the Golgi for O-glycosylation.
After modification in the Golgi, plasma proteins are:
Sorted and sent to their respective destinations: secreted from the cell (extracellular), incorporated into the cell membrane, targeted to lysosomes for recycling (defect causes I-cell disease!)
Plasma proteins function in: (4)
- Cell-surface recognition
- Cell-surface antigenicity
- Components of the ECM and mucins (for lubrication)
- Globular proteins in plasma
Plasma proteins are degraded by:
Lysosomal hydrolases, which can be affected by hereditary enzyme deficiencies that cause oligosaccharidoses
Plasma proteins are derived from which sugar?
Mannose
Describe the sugar conversion pathway in the making of plasma proteins (5)
- Mannose is phosphorylated to mannose-6-phosphate
- M6P then isomerizes to M1P
- M1P then becomes GDP-mannose (GTP donation?)
- GDP-mannose then becomes GDP-4-keto-6 deoxymannose
- GDP-4-keto-6-deoxymannose is then converted to GDP-fucose, which eventually goes on to form plasma proteins (glycoproteins)
What is dolichol phosphate?
Dolichol phosphate is the backbone of glycoprotein synthesis. Responsible for synthesis of the high mannose form of oligosaccharides in the RER.
Plasma protein solubility and charge effects (3)
- Plasma proteins are highly negatively charged: sugars contain many -OH groups
- Hydrophilic
- Water acts as a buffer and space filter (funnel) between transmembrane plasma proteins and molecules (like growth factors): The space helps with plasma protein recognition of molecules and consequential signaling
Albumin characteristics and function (5)
- Small, water soluble plasma protein with a long half-life
- 60% of total plasma protein
- Provides 70-80% of total osmotic pressure of plasma; helps maintain BP
- Binds free FAs, Ca2+, zinc, steroid hormones, copper, and bilirubin
- Many drugs can bind to albumin as well: decreases drug effectiveness and may lengthen lifetime in circulation
Coagulation factors synthesized in the liver (classes [4] and agents)
- Procoagulants: fibrinogen; prothrombin; factors V, VII, VIII, IX, X, XI, XII, XIII; thrombopoietin
- Anticoagulants: protein C, protein S, tissue factor pathway inhibitor, anti-thrombin
- Pro-fibrinolysis: Factor XIIa, plasminogen
- Anti-fibrinolysis: plasminogen activator inhibitor-1, alpha-antiplasmin, tissue activatable fibrinolysis inhibitor
Acute phase proteins are induced by:
Injury, toxins, or pathogens
What is the acute phase response?
Injury, toxins, or pathogens increase the levels of IL-6 which induce hepatocytes to increase clotting factors, complement proteins, acute phase proteins, and decrease albumin. This pathway stimulates bone marrow to also increase leukocytosis.
Simultaneously, the brain is participating in thermoregulation and sickness behavior.
What are some acute phase proteins? (7)
- Complement proteins: C3, 4, 9
- Iron-binding proteins: ferritin, haptaglobin
- Antimicrobial proteins: antimicrobial peptide 2, hepcidin
- Clotting factors
- Inflammatory proteins: IL-6, LPS-binding protein, phospholipase A2
- Lectins, pentraxins, ficolins, and collectins: CRP, mannose-binding lectin
- Protease inhibitors: alpha2-macroglobulin, alpha1-antichymotryosin, and alpha1-antitrypsin
What is I-cell disease?
Deficiency of phosphotransferase that stops mannose from being converted to M6P in the RER. As a result, synthesis of glycoproteins (plasma proteins) is halted. Patients presents with skeletal abnormalities, restricted joint movement, coarse facial features, and severe psychomotor impairment. Typically results in early childhood death.
How does rheumatoid arthritis related to glycoproteins?
RA is an autoimmune reaction with a mannose-binding protein deficiency. This deficiency results in decreased glycoprotein (plasma protein) synthesis. Decreased glycoproteins then cause decreased production of mucin, which help with joint lubrication, leading to stiff, inflamed joints.
What are genetic lysosomal hydrolase deficiency?
Deficiencies in lysosomal hydrolase cause intracellular glycoprotein accumulation, leading to toxicity. Manifests as mannosidoses, fucosidosis, aspartylglucosaminuria, sialidosis, Schindler disease. Can be treated with gene therapy, enzyme replacement therapy, and small molecules designed for reactivating defective enzymes.
