L6 Protein catabolism & urea cycle

Overview of CHEM1829 Lecture 06

  • Topic: Protein Catabolism & Urea Cycle

  • Institution: Scientia, UNSW Sydney

  • Lecturer: Dr. Gee Chong Ling (g.ling@unsw.edu.au)

  • Visual Aid: Human Metabolic Pathway Map by Stanford Medicine

  • Related Processes:

    • Glucose

    • Acetyl CoA

    • Urea Cycle

    • Oxidative Phosphorylation

    • Fatty Acid Synthesis

    • Amino Acid Synthesis & Breakdown

    • Nucleic Acid Synthesis

  • Key Point: The pathway to energy generation varies based on enzymatic regulation and time.

Learning Outcomes

  • Protein Catabolism Learning Outcomes:

    • LO1: Describe the breakdown of dietary proteins.

    • LO2: Discuss the process of protein turnover.

    • LO3: Explain the function of ubiquitin and the proteasome.

  • Urea Cycle Learning Outcomes:

    • LO1: Explain how an amino group is removed from an amino acid.

    • LO2: Outline degradation of amino acids in muscle during prolonged exercise & fasting.

    • LO3: Outline the Urea cycle, including ATP used, location of synthesis, and source of the two N atoms in urea.

Breakdown of Dietary Proteins

Protein Metabolism

  • Definition: A type of complex macromolecule, serving as an energy source for human metabolism.

    • Key Functions:

    • BUILD UP: Muscle, enzymes, etc.

    • BREAKDOWN: Provides energy source.

Protein Breakdown Process

  • Transition: Proteins are broken down from complex macromolecules to amino acid monomers.

  • Amino Acid Structure:

    • Composed of:

    • Amino group (NH2)

    • Carboxyl group (COOH)

    • Side chain (R group)

  • Color Coding of Atoms:

    • Oxygen: Red

    • Carbon: Grey

    • Nitrogen: Blue

    • Hydrogen: White.

Fate of Amino Acids

  • Storage: Amino acids cannot be stored in the body and cannot be directly excreted.

  • Reactions: Can enter pathways like carbohydrate catabolism or DNA synthesis.

Types of Dietary Proteins

  • Essential Amino Acids: Cannot be synthesized by the body and must be ingested.

  • Non-Essential Amino Acids: Can be synthesized in the body from essential amino acids.

  • Main Food Sources for Proteins:

    • Eggs, Soy Protein, Parmesan, Sesame seeds, Peanuts

    • Specific Essential Amino Acids:

    • Histidine, Isoleucine, Leucine, Lysine, Methionine, Phenylalanine, Threonine, Tryptophan, Valine.

    • Specific Non-Essential Amino Acids:

    • Alanine, Arginine, Asparagine, Aspartate, Cystine, Glutamic Acid, Glycine, Ornithine, Proline, Serine, Tyrosine.

Protein Digestion Phases

In the Stomach

  • Environment:

    • Acidic (HCl present).

  • Enzyme:

    • Pepsin (activated from pepsinogen).

In the Intestine

  • Enzymes:

    • Proteolytic enzymes from the exocrine pancreas reach the duodenum.

    • Proteases are embedded in the plasma membrane of the intestinal cells.

  • Process:

    • Proteolytic enzymes are synthesized as zymogens.

    • Require activation by cleavage to hydrolyze proteins into amino acids, dipeptides, and tripeptides.

Zymogen Activation

  • Process:

    • Enteropeptidase activates trypsinogen to trypsin in the duodenum.

    • Trypsin activates more trypsinogen and other zymogens progressively.

  • Importance of Regulation:

    • Proteolytic enzymes are only active in their functional locations to prevent premature degradation of proteins.

Complete Protein Breakdown

Absorption & Transport

  • Mechanism:

    • Amino acids, di- and tri-peptides are absorbed from the lumen of the intestine into intestinal cells.

    • Cleavage of oligopeptides occurs by intestinal aminopeptidase.

    • Amino acids are transported from intestinal cells to the bloodstream via specific transporters.

Protein Turnover

Overview

  • Definition: Continuous process of protein synthesis and degradation in cells.

  • Significance:

    • Supplies amino acids for bodily functions and contributes to homeostasis.

  • Half-lives of Proteins:

    • Varies widely among different proteins (e.g., Crystallin has a long half-life while Ornithine decarboxylase has a half-life of about 11 minutes).

Functional Roles

  • Functions:

    • Essential for organ formation, cell cycle progression, cholesterol metabolism, and circadian rhythms.

Ubiquitin-Proteasome System

Ubiquitin Function

  • Mechanism:

    • Marks proteins for degradation, enabling regulated protein turnover.

  • Coordinated Process:

    • Requires ATP for the marking and migration processes.

  • Characteristics:

    • Ubiquitin is a small protein (approximately 8.5 kDa) which attaches to the target protein's amino groups via an isopeptide bond.

Proteasome Activity

  • Role:

    • The proteasome digests Ub-tagged proteins.

    • Unfolds and progressively breaks down proteins while recycling ubiquitin components.

Removal of Amino Group: Urea Cycle

Overview

  • Goal:

    • Converts amino groups from amino acids into urea for excretion.

  • Location:

    • Primarily occurs in the liver.

Steps in the Urea Cycle

  1. Carbamoyl Phosphate Synthesis

    • Consumes NH4+ and bicarbonate (HCO3-) yielding carbamoyl phosphate.

    • This reaction occurs in mitochondria, using 2 ATP.

  2. Citrulline Formation

    • Catalyzed by ornithine transcarbamoylase, transferring carbamoyl group to ornithine forms citrulline.

  3. Argininosuccinate Synthesis

    • Citrulline combines with aspartate via argininosuccinate synthetase, donating the second nitrogen in urea while cleaving ATP to AMP and PPi.

  4. Urea Cleavage

    • Argininosuccinate is converted to arginine and fumarate, followed by conversion of arginine to urea and ornithine via arginase.

Stoichiometry of the Urea Cycle

  • Overall Reaction:
    extCO<em>2+extNH</em>4++extaspartate+3extATP+2extH2extO<br>ightarrowexturea+2extADP+2extPi+extAMP+extPPi+extfumarateext{CO}<em>2 + ext{NH}</em>4^+ + ext{aspartate} + 3 ext{ATP} + 2 ext{H}_2 ext{O} <br>ightarrow ext{urea} + 2 ext{ADP} + 2 ext{Pi} + ext{AMP} + ext{PPi} + ext{fumarate}

  • ATP Consumption:

    • Total of 4 ATP equivalents used in the synthesis of one molecule of urea due to the hydrolysis of pyrophosphate (PPi).

transcript of lecture:

So that's a good news.

At least I break it down to you.

So, so the good news is you can follow the

nitrogen ion, right?

Um, using this sort of process, and you know, the

whole process is about putting into the right place, doing

the right job, and then cleave off.

This is a structure that can get rid of in

the urea form.

OK, so now, by this time.

You already chop chop chop chop chop, you've chopped up

your proteins, you take the good part which is the

carbon skeleton, you use it as an energy source.

Now, the urea, because you can't use it, if we

accumulate that, it becomes toxic to our body.

We need to get rid of it.

That's why we go through the urea cycle to get

rid of that.

OK, so that's the whole purpose of the two parts

of this lecture.