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I. Cholesterol

A. Rate Limiting Step of Cholesterol Synthesis

  1. Production of Mevalonate
       - Enzyme(s): HMG-CoA reductase
       - Substrate(s): HMG-CoA
       - Product(s): Mevalonate

B. Lipid Particles

  1. Chylomicron
       - Formation: Synthesized in the gut during fed state
       - Transport: Carries free fatty acids; liver cells have receptors to take up remnants via endocytosis

  2. VLDL
       - Formation: Produced in the liver due to excess carbohydrates or fats in the fed state
       - Transport: Secreted into the bloodstream, delivers fatty acids to adipose tissue and other cells (muscle and capillary beds)
       - Liver uptake: 50% cleared by liver via apoE; remaining undergo further TAG removal to become IDL

  3. IDL
       - Formation: Arises when remnants of VLDL lose additional core TAGs
       - Transition: Converts to LDL after TAG loss

  4. LDL
       - Formation: Generated from IDL after removal of TAGs
       - Function: Delivers cholesterol and cholesterol esters; about 40% uptake by tissues via apoB100 receptors (important for membrane synthesis and Vitamin D synthesis), with the remaining 60% returned to the liver
       - Implication: Excess LDL can saturate receptors, prompting nonspecific uptake by macrophages

  5. HDL
       - Synthesis: Initiated in the liver and intestine; nascent HDL has very low levels of TAGs and cholesterol esters
       - Maturation Process: Nascent HDL collects phospholipids and cholesterol from cells also facilitated by LCAT (which converts free cholesterol)
       - Removal: Cleared from circulation by SR-B1 until depleted of cholesterol and its esters

C. Formation of Cholesterol Esters

  1. In the Liver
       - Catalyzed by: ACAT
       - Reaction: Transfers fatty acid from coenzyme A to the hydroxyl group of cholesterol

  2. In HDL Particles
       - Catalyzed by: LCAT
       - Process: Converts free cholesterol and lecithin from chylomicron and VLDL remnants into cholesterol esters

D. HDL and LDL Interaction in Cholesterol Transport

  1. HDL's Role: Transfers free cholesterol from cells and delivers it to the liver and VLDL/VLDL remnants via CETP

  2. LDL's Role: Responsible for delivering cholesterol to peripheral tissues

E. Enzymes Responsible for Cholesterol Removal from Cell Membranes

  1. ABC1 (ATP Binding Cassette Protein 1)
       - Function: Uses ATP hydrolysis to transfer cholesterol from the inner to the outer leaflet of the cell membrane

  2. LCAT: Fields within HDL for trapping cholesterol in the core

F. Reverse Cholesterol Transport

  1. Mechanism:
       - HDL removes excess cholesterol from cells, primarily those overloaded with cholesterol
       - Enzyme and Reaction Involvement:
          - ABC1 transfers cholesterol to nascent HDL which turns into a cholesterol-rich HDL particle, returns to the liver.
          - Enzyme: LCAT
          - Substrate(s): Free cholesterol (from HDL) and lecithin
          - Product(s): Cholesterol ester, lysolecithin
       

  2. Low Intracellular Cholesterol Levels: SCAP escorts SREBP from the ER to the Golgi, cleaved by S1P and S2P, enabling increased gene transcription for synthesis and uptake

G. Regulation of Cholesterol Synthesis

  1. Transcription Control
       - Factors: SREBPs, SRE, SCAP, S2P
          1. Cholesterol binds ER, leading to SREBP cleavage and triggering gene transcription of HMG-CoA reductase and the LDL receptor
       - Mechanism:
          1. HMG-CoA reductase localized on the ER membrane undergoes oxidative degradation when sterols bind.
     

  2. Covalent Modification
       - During fasting: AMP-activated protein kinase converts into its active form, influencing cholesterol synthesis
       

H. Rate Limiting Step of Sterol Hormone Synthesis

  1. Enzyme Involvement: (additional enzymes listed) non-P450 enzymes in the process

  2. Location: Primarily occurs in adrenals and gonads

II. Protein and Single Carbon Donors

A. Urea Cycle

  1. Overview:
       - Takes place in the liver mitochondria, converting ammonia to urea for waste disposal
       - Compromise between ammonia detoxification and urea excretion occurs in the cytosol

  2. Sources of Nitrogen
       - 1 from ammonium (NH₄⁺) and 1 from aspartate

  3. Key Enzymes and Products
       - Carbamoyl Phosphate Synthetase I (CPS-1):
          * converts NH₄⁺, CO₂, and ATP into carbamoyl phosphate (first step)
       - Ornithine Transcarbamoylase (OTC):
          * combines ornithine and carbamoyl phosphate to form citrulline
       - Argininosuccinate Synthetase:
          * combines citrulline and aspartate to form argininosuccinate
       - Argininosuccinate Lyase:
          * cleaves argininosuccinate into arginine and fumarate
       - Arginase:
          * hydrolyzes arginine to yield urea and regenerate ornithine

  4. Regulation
       - N-acetylglutamate (NAG) acts as a positive allosteric regulator for CPS-1
       - Enzyme expression correlates with dietary protein intake:
          - High protein diet increases enzyme expression; low protein induces a decrease
          - During starvation: enzyme activity increases

  5. Enzyme Dysfunction
       - Lack of any enzyme can lead to fatality shortly post-birth
       - Ornithine Transcarbamoylase Deficiency: Type 2 Hyperammonemia (x-linked)
       - Carbamoylphosphate Synthetase Deficiency: Type 1 Hyperammonemia (CPSD)

B. Alanine-Glucose Cycle

  1. Muscle During Exercise/Fasting:
       - Amino acids undergo breakdown → nitrogen shifts to pyruvate → alanine → circulates to liver

  2. Liver Function:
       - Takes up alanine, removing nitrogen to generate pyruvate → glucose production through gluconeogenesis

C. Glutamine and Glutaminase Cycle

  1. Brain:
       - Critical for ammonia management and glutamate synthesis, crucial for neurotransmission

  2. Kidney:
       - Essential for acid-base balance during acidosis; involves bicarbonate preservation

D. Formation of Ornithine in the Urea Cycle

  1. Regeneration:
       - Through breakdown of arginine by arginase which yields ornithine, transporting it back to mitochondria for urea cycle work

E. Connection Between Urea Cycle and TCA Cycle

  1. Fumarate and OAA Relationship:
       - Urea cycle connects to TCA through fumarate, and the net effect returns OAA to the TCA cycle

F. Amino Acid Formation and Degradation

  1. Serine to Glycine Formation:
       - Method: 3-phosphoglycerate through dehydrogenase produces serine; serine can create pyruvate or yield glycine, which involves tetrahydrofolate (FH4)
       - Glycine Degradative Pathways: Glycine can convert to CO₂ and NH₄⁺, influencing oxalate formation leading to kidney stones

  2. Cysteine Formation:
       - From methionine through homocysteine; involves vitamin B6, folate, B12, degrading to several products including pyruvate and sulfate
       

  3. Glutamate and Glutamine Formation:
       - Glutamate forms from transamination of α-ketoglutarate and may return to this cycle; glutamine is produced from ammonia uptake, influencing cyclic action in the kidney

  4. Phenylalanine and Tyrosine Pathways:
       - Critical for metabolic pathways involving degradation into glucogenic and ketogenic products

G. Importance of BCAA in Energy Metabolism

  1. Muscle Role During Exercise:
       - BCAAs converted to energy substrates when needed
       - Transamination forms glutamate and aspartate which links to the purine nucleotide cycle

H. Role of Tryptophan in Niacin Deficiency

  1. Conversion Mechanism:
       - Tryptophan's conversion into niacin provides essentials when dietary niacin is insufficient, supporting NAD/NADP homeostasis

I. General Health Conditions Associated with Amino Acid Metabolism

  1. Various Genetic Disorders:
       - Include Discussed metabolic pathways for phenylalanine, methionine, and others with detailed mention of clinical impacts and necessary enzyme functions
       

III. Purine and Pyrimidine

A. Purine Synthesis

  1. Mechanism:
       - Synthesized from PRPP; ribonucleotides formed from this substrate stepwise into IMP, then to AMP and GMP

B. Purine Degradation

  1. Metabolic Pathways:
       - AMP and GMP undergo several deamination and phosphorylation steps leading to uric acid generation via xanthine oxidation
       - Clinical Relevance: Hyperuricemia in gout and Von Gierke disease

C. Purine Recycling and Associated Diseases

  1. Salvage Pathways:
       - Utilize phosphoribosyltransferases for recycling, deficiencies leading to significant clinical syndromes like Lesch–Nyhan syndrome and ADA deficiency
       

D. Pyrimidine Synthesis

  1. Process:
       - Bases created first with carbamoyl phosphate from CPS II and aspartate, then assembled into ribonucleotides

E. Pyrimidine Degradation

  1. End Products:
       - Dephosphorylated nucleotides yield ribose 1 P and a variety of non-toxic excretory products

IV. Hormones Part I

A. Growth Hormone (GH)

  1. Signals for Production:
       - Low blood glucose, high blood amino acids, exercise, sleep, stress stimulate GH release; various hormonal influences noted

  2. Hypothalamus Role:
       - Secretes GHRH to stimulate GH release, and somatostatin inhibition indicated

  3. Pituitary Role:
       - Somatotrophs release GH in response to hypothalamic action, with IGF-1 feedback regulation

  4. GH Susceptibility in Different Tissues:
       - Liver, muscles, adipose, and bone responses delineated

B. Thyroid Hormone

  1. Production Signals:
       - TSH regulates thyroid hormone synthesis initiated by TRH from the hypothalamus

  2. Tissue Impact:
       - In essential metabolic control outcomes for liver, muscle, and adipose noted, alongside circadian patterns in regulation emphasized

V. Coagulation Part I

A. Platelet Formation

  1. Mechanism:
       - Megakaryocytes produce platelets within BM, crucial for hemostasis

B. G Protein Receptors on Platelets

  1. Thrombin Interaction:
       - Thrombin binds PARs, triggering granule release and shaped activation cascade
     

C. Role of Liver and Vitamin K in Clotting

  1. Factor Activation:
       - Specific clotting factors require vitamin K for necessary modifications pre-release
     

D. Coagulation Initiation Mechanisms

  1. Intrinsically and Extrinsically Triggered:
       - Differential pathways described with emphasis on factor interactions and cellular signaling specifics

VI. Coagulation Part II

A. Clot Formation Overview

  1. Fibrin Degradation:
       - Fibrinogen leads to soft clot formation, with factors influencing transformation into a hard clot

B. Regulation of Thrombin Activity

  1. Protein C/S Pathway:
       - Protein C activation critical for feedback control in the cascade
     

C. Targeting Enzymes for Regulation

  1. Role of Antithrombin in Inhibition:
       - Specific proteolytic pathways affecting thrombin and factor levels discussed