Creatine Metabolism and Collagen Diseases Requirements (Dar Al Uloom University) PDF

Creatine metabolism and Collagen Diseases Requirements Musculoskeletal Block (MUSC 115) Department of Biochemistry College of Medicine 2024/2025 1  Objectives of the lecture: Study the importance of creatine...

Creatine metabolism and Collagen Diseases Requirements Musculoskeletal Block (MUSC 115) Department of Biochemistry College of Medicine 2024/2025 1  Objectives of the lecture: Study the importance of creatine in muscle as a storage form of energy Understand the biosynthesis of creatine Study the process of creatine degradation and formation of creatinine as an end product Understand the clinical importance of creatinine as a sensitive indicator of kidney function Study the structure, function, types, and biosynthesis of collagen Understand different diseases associated with collagen 2  Distribution of Body Creatine Creatine: Kidney s Is a nitrogen containing compound that is synthesized in liver and kidney. Loading… Liver It is transported from liver to other tissues, 98% present in skeletal and heart muscles. The phosphorylated derivative of creatine (creatine phosphate) is a high-energy Muscle compound found in skeletal muscles. Energy End product source 3  Creatine Biosynthesis Kidney Three amino acids are required: s 1- Glycine 2- Arginine 3- Methionine (as s-Adenosylmethionine) Liver Sites of biosynthesis: Step 1: Kidneys Step 2: Liver Muscle Energy End product source 4  Creatine phosphate A high-energy phosphate compound. Creatine Acts as a storage form of energy in the muscle (main storage form for intense and immediate muscular AT AT contraction). Loading… P P Creatine Kinase ADP + AD H+ Provides small but, ready source of energy to P maintain the intracellular level of ATP during the first few minutes of intense muscular contraction. Creatine phosphate The amount of creatine phosphate in the body is 5  Creatine Degradation o Creatine and creatine phosphate spontaneously form creatinine as an end product. o Creatinine is excreted in the urine. o Serum creatinine is a sensitive indicator of kidney disease (kidney function test). o Serum creatinine increases with the impairment of kidney function.  Urinary Creatinine A typical male excretes about 15 mmol of creatinine per day. A decrease in muscle mass due to muscular dystrophy or paralysis leads to decreased level of creatinine in urine. The amount of creatinine in urine is used as an indicator for the proper collection of 24 hours urine sample.  Creatine Kinase (CK) o CK is responsible for the generation of energy in Creatine contractile muscular tissues. o CK levels are changed in disorders of cardiac and AT AT P P skeletal muscle. Creatine Kinase o CK has 3 isoenzymes: AD ADP + H+ P CK-MM mainly in skeletal muscle CK-MB mainly in heart muscle Creatine phosphate CK-BB mainly in brain 8  Collagen: Overview o Most abundant protein in the human body. o Collagens are highly stable molecules with half-lives as long as several years. o A fibrous protein that serves structural functions. o It is part of connective tissues, bone, teeth, cartilage, tendons, skin, blood vessels. o It has a long and rigid structure. 9  Collagen Structure o Collagen α-chain (~1,000 amino acids long) is rich in proline and glycine. o The glycine residues are part of a repeating sequence:–Gly–X–Y–, where X= frequently proline and Y= often hydroxyproline can be also hydroxylysine. o Collagen consists of three α-chains wound around one another in a rope-like triple helix held together by hydrogen bonds. 10  Non-standard Amino Acids in Collagen o Proline and lysine are converted to hydroxyproline and hydroxylysine; by hydroxylase enzymes during post-translational modifications. o Loading… The enzyme requires vitamin C for its function. 11  Types of Collagen o Types of collagen depend on their functions. o Variations in the amino acid sequence of a- chains result in different properties. o Examples: Type I: (a1)2 (a2)1 Type II: (a1)3  Biosynthesis of Collagen Collagen is synthesized in fibroblasts, osteoblasts, chondroblasts: Pre-pro Pro Mature collagen. Polypeptide precursors (Pre-pro) are enzymatically modified to form triple helix which is secreted into the extracellular matrix as procollagen. Procollagen is cleaved by N- and C- procollagen peptidases to release tropocollagen molecules. Tropocollagen molecules spontaneously associate to form collagen fibrils. This produces mature collagen. Biosynthesis of Collagen 14 Biosynthesis of Collagen 15  Crosslinking of Collagen Fibrils Lysyl oxidase oxidatively deaminates some of the lysine and hydroxylysine residues in collagen. The reactive aldehydes – allysine and hydroxyallysine condense with lysine or hydroxylysine residues in neighboring collagen molecules to form covalent cross-links this produces mature collagen fibers. mature collagen fibres  Collagen Diseases Two types of collagen diseases: 1-Acquired disease: The deficiency in vitamin C will cause Scurvy disease. 2-Geneticlly inherited diseases: Ehlers-Danlos syndromes (EDS) Osteogenesis imperfecta (OI)  Collagen Diseases Ehlers-Danlos syndrome is duo to: o Deficiency of lysyl hydroxylase or N-procollagen peptidase o Mutations in the amino acid sequence of collagen I , III , V o Characterized by: Hyper-extensibility (the skin can become stretched) of skin and joints.  Collagen Diseases Osteogenesis imperfecta (brittle bone disease): Bones fracture easily with minor or no trauma Mutations replace glycine with another amino acids having bulky side chains preventing the formation of triple helical conformation. It has three types: Type I (most common): characterized by mild bone fragility, hearing loss and blue sclerae. Type II (most severe): lethal in the perinatal period (fractures in utero). Type III (severe form): fractures at birth, short stature, spinal curvature leading to a humped back (kyphotic) appearance and blue sclerae.  References Lippincott, page 287-288 Bishop 6th edition, page 223-227