Phenylketonuria (PKU) is an inherited metabolic disorder caused by a recessive gene, meaning a child must inherit a copy of the mutated allele from each parent to develop the condition. Individuals with PKU lack the enzyme needed to metabolize the amino acid phenylalanine. If the condition is not treated through a regulated diet, the resulting buildup of phenylalanine in the brain becomes toxic, leading to severe consequences such as significant deficits in cognitive function, intellectual disability, seizures, and an increased risk of various psychiatric disorders.

Phenylketonuria (PKU)

- Absence of enzyme homogentisate oxigenase
- Excreted in urine and produces melanin-like dark pigment when oxidized by air - black urine
- Relatively benign disease as homogentisate can be excreted


Alkaptonuria

Maple syrup urine disease is an inborn error of amino acid catabolism characterized by a missing or defective branched-chain $$\alpha$$-keto acid dehydrogenase complex. Due to this deficiency, the oxidative decarboxylation of $$\alpha$$-ketoacids from the branched-chain amino acids (Ile, Val, and Leu) does not occur, leading to a build up of these $$\alpha$$-ketoacids and branched-chain amino acids in the blood and urine. The condition is associated with severe mental deficiency and failure to thrive, but it can be detected through screening in newborn (NB) blood samples and managed with a restricted diet.

Maple Syrup Urine Disease

- Phenylketonuria (PKU)
- Alkaptonuria
- Maple-Syrup urine disease

Michigan State University

Amino acids make up every protein. There are 20 total amino acids each with a unique side-chain group. Some additional amino acids are listed, but only 20 are coded from DNA directly. These side-chains allow for chemical interactions like sulfide bonds, hydrogen bonds, and ionic bonds. Amino acids are further divided by being non-polar, polar, and charged. They link together with a peptide bond making a string of amino acids a polypeptide. Finally, each amino acids is assigned a name, a three-letter symbol and a one-letter symbol. 


Amino Acids are involved in many systems and issues with its breakdown can cause diseases: 
- In the liver: major site of urea production in the urea cycle
- Alpha-keto acids can deliver amino groups to the liver 
- Ammonium is toxic: lethargy, headache, vomiting, seizures, death
- Seen in compromised liver


Amino Acids

- Enzyme: Glutamate dehydrogenase
- 1. Oxidation (NAD+ or NADP+) of glutamate to yield Schiff-base intermediate
- 2. Hydrolysis deamination of intermediate to make alpha-ketoglutarate
- Glutamate -> alpha-ketoglutarate and ammonium
- Mitochondrial enzyme: NH4+ is toxic
> Reactions close to equilibrium

> Usually pulled forward by loss of NH4+


Oxidative deamination of amino acids to yield glutamate in liver

- 1st amino group from ammonium, second amino group from aspartate, carbon comes from bicarbonate
- ** Fumarate is formed from the breakdown of argininosuccinate in the urea cycle, and links the urea cycle with the TCA cycle
- First reactions occur in the mitochondrial matrix

OVERVIEW
- Carbamoyl Phosphate synthesis
- Formation of Citrulline (in mitochondrial matrix)
- Formation of Argininosuccinate (cytoplasm)
- Formation of Fumarate
- Cleavage

- Eventually converted to OAA, cycle can start again


Urea Cycle

Inborn Errors of Amino Acid Catabolism

Protein structure is the 3-dimensional assembly caused by the string of amino acids translated from RNA . Protein structures varies immensely due to the assembly of the amino acids.
There are four subdivisions of proteins structures:
- Primary structure
- Secondary structure
- Tertiary structure 
- Quaternary structure 

Protein Structure 

An amino acid is an organic molecule containing a hydrogen atom, a carboxyl group ($$\text{–COOH}$$), and an amino group ($$\text{–NH}_2$$) all bonded to the same central carbon atom, called the $$\alpha$$ carbon. The fourth variable group attached to the $$\alpha$$ carbon is called a residue or side chain and is represented in structural formulas by the letter $$\text{R}$$.

Amino Acid Structure

A residue is a monomeric unit that results when two or more amino acids combine and release a water molecule during dehydration synthesis. The primary structure of a protein, which is a peptide chain, is composed of these amino acid residues.

Amino Acid Residue

A side chain, or residue (represented as $$\text{R}$$ in structural formulas), is the variable fourth group bonded to the central $$\alpha$$ carbon of an amino acid. These groups are composed primarily of carbon, hydrogen, oxygen, nitrogen, and sulfur in the form of hydrocarbons, acids, amides, alcohols, and amines. Their unique chemical properties allow them to form hydrogen, ionic, and disulfide bonds, along with polar/nonpolar interactions that are essential for folding proteins into secondary, tertiary, and quaternary structures.

Side Chain

A peptide bond is a covalent chemical bond formed when the carboxylic acid group of one amino acid reacts with the amine group of another, releasing a water molecule in a dehydration synthesis process.

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