11) Nitrogen Metabolism 3

Essential amino acids

Body cannot synthesize; must get from dietary intake

The essential amino acids are:

Leucine Isoleucine Valine (BRANCHED CHAIN AMINO ACIDS)

Phenyalanine Tryptophan (Aromatics; Tyrosine not included because it can be synthesized from Phenylalanine)

Methionine (source of sulfur)

Lysine Arginine Histidine (positive charges)

Threonine (has a side chain with a chiral carbon)

Arginine

Not required for adults but is required for growth in children

Nonessential amino acids

We still need them, but our body can synthesize them

Non essential amino acids

serine, cysteine, alanine, and their metabolically close relative glycine (three carbon amino acids)

aspartate and asparagine (the four carbon amino acids)

glutamate, glutamine, proline, and their close relative arginine (the five carbon amino acids)

tyrosine (made from phenylalanine)

Tyrosine is made from _______ which is an _________ __________ _________

phenylalanine; essential amino acid

Amino acid metabolism

depends on the activities of many enzymes, often working in conjunction with co-factors, to prevent accumulation of potentially toxic molecules.

Disruption of enzyme function can lead to

accumulation of toxic substrates, resulting in disease; this mechanism is common to many disorders of amino acid metabolism.

Treatments for amino acid metabolism disorders, when possible, are often aimed at

minimizing accumulation of toxic substrates by limiting availabilities of their precursors, or by promoting degradation of the toxic substrates.

Branched-chain amino acid (BCAA) metabolism in muscle:

1. BCAA’s are deaminated and metabolized in _______ and _______ to drive ____ __________.

2. Amine groups are transferred to _________ to generate _________

3. __________ can be released into the bloodstream; absorbed by liver

4. In the liver, alanine is broken down to _________(drives ______________); excess NH3 drives formation of _____

1. muscle and brain; ATP production.

2. pyruvate; alanine

3. Alanine

4. pyruvate; gluconeogenesis; urea

All essential amino acids make

glucogenic substrates

_________ ___________ and _____________ have side chains that are carbon groups that make a branch

Leucine, isoleucine, and valine

Leucine—>

ketogenic amino acids

isoleucine—>

ketogenic and glucogenic substrates

Cori cycle

Conversion of pyruvate to lactate in muscle, transport of lactate to the liver and conversion to glucose.

BCAA’s are converted to ___________ ___________ in muscle (and brain) and used for fuel

carbon skeletons

Cahill cycle

Ammonium is transferred to pyruvate to make alanine, transported to liver

De-aminated to make pyruvate. ammonia is packaged to urea,

Overall metabolism of BCAA’s:

1. Transamination: generates ____________

2. Alpha-ketoacids must next be metabolized by ____________ _______________

3. Carbon skeletons are metabolized to form propionyl coA -> ____________ or __________ __________ to drive TCA cycle

1. “alpha-ketoacids”.

2. alpha-ketoacid dehydrogenase

3. succinyl coA (Val, Ile) or ketone bodies (Ile, Leu)

Fill in the blanks

Transamination

generates “alpha-ketoacids”

Alpha-ketoacids must next be metabolized by _______________

alpha-ketoacid dehydrogenase

Carbon skeletons are metabolized to form

propionyl coA -> succinyl coA (Val, Ile)

OR

ketone bodies (Ile, Leu) to drive TCA cycle

Key Steps of BCAA Metabolism:

1. Take off amine group (transamination) to make an a-keto

2. Remove carboxylate group (via decarboxylation). This is achieved by a-ketoacid dehydrogenase

3. Form ketone bodies to drive TCA

Maple Syrup Urine Disease

Hereditary variant causing decrease in α-ketoacid dehydrogenase activity.

Symptoms include feeding difficulties, developmental delay, convulsions, failure to thrive.

Name of the disease comes from the characteristic sweet odor (like maple syrup or burnt sugar), due to accumulation of branched-chain alpha-ketoacids and by-products.

Treatment requires special low-protein diet, to limit levels of branched-chain amino acids.

Maple Syrup Urine Disease Treatment

Requires special low-protein diet, to limit levels of branched-chain amino acids.

Catecholamine biosynthesis

Conversion of phenylalanine to tyrosine depends on phenylalanine hydroxylase

Classical phenylketonuria (PKU)

Phenylalanine hydroxylase is defective

Phenylalanine (Phe) cannot be converted to tyrosine. Phe is converted to other products such as phenylpyruvate and phenylacetate (ketones which can accumulate in urine), which can accumulate to toxic levels.

Newborns with complete lack of enzyme activity develop symptoms within a few months if untreated; intellectual disability, developmental delay, pigmentation deficit. Screening test of newborns for PKU is routinely performed. Partial deficiencies also exist, may show up in later childhood.

Classical phenylketonuria (PKU) Treatment

Diet must restrict levels of phenylalanine, with supplementation of tyrosine.

Aspartame (Nutrasweet) contains phenylalanine equivalents and must be avoided because they will be metabolized to phenylalanine when ingested

*Tyrosine now becomes essential

_________________ contains phenylalanine equivalents and must be avoided in people with PKU

Aspartame (Nutrasweet)

Alkaptonuria

Defect in homogentisate dioxygenase (in Tyr degradation pathway); leads to accumulation of homogentisate in tissues, bone, urine.

Homogentisate turns dark brown/black upon oxidation (to “alkapton”, oxidation product). Urine turns black after exposure to air.

Alkapton can also accumulate in cartilage, bone, sclera.

Can precipitate, leading to arthritis, also damage to heart valves and kidneys; sialolithiasis (stones in salivary gland) can also occur.

Homocysteine metabolism:

1. Homocysteine is an intermediate metabolite in the generation of______

2. It is metabolized to ___________ (by ___________ ____________) This metabolism depends on ________, which is derived from dietary vitamin B6.

3. Can also be metabolized from _____

1. SAM

2. cystathionine; cystathionine synthase; PLP (pyridoxal phosphate)

3. B12

Fill in the blanks

(a)

Homocystinuria (HCU)

Defect in cystathionine synthase, leads to accumulation of homocystine (oxidized homocysteine) in blood and urine.

HCU symptoms

Risk of cardiovascular disease and thromboembolisms (25% mortality by age 30).

Linked to pectus excavatum (see above); lens dislocation is frequent (90%). Mechanisms underlying these are unclear.

HCU Treatment

High dose of vitamin B6, aimed at maximizing activity of defective enzyme. Also treated by decreasing intake of methionine, increase intake of B12, folic acid, to metabolize HC through methionine synthase pathway.

Elevated purine degradation can lead to _______

gout

Purine nucleotides can either be ________ or __________

recycled or degraded

The major purine degradation product is _____ _______, formed by xanthine oxidase.

uric acid

Uric acid is a by-product of _________ ____________

Nucleotide metabolism

Insolubility of uric acid leads to its ___________ in joints, can lead to __________/___________

precipitation; inflammation/gout (sometimes a side effect of diuretics).

Allopurinol

drug that inhibits xanthine oxidase (treatment for gout).

Two Methods of Allopurinol Inhibition of xanthine oxidase

1. hypoxanthine —//—> xanthine

2. xanthine —//—> uric acid

Hypoxanthine and xanthine excreted in urine

These two methods result in less uric acid build-up

Uric acid is in fact acidic, and what we actually have is _______, generally __________. Both “sodium urate” and uric acid are used to describe the compound.

urate; NaUrate

Hypercatabolic state

Syndrome; HS

Characterized by increased fuel utilization and negative nitrogen balance (nitrogen excreted is greater than the amount consumed). HS occurs following trauma, surgery, or critical illness.

Enough protein =

enough nitrogen

Not enough protein =

excretion of more nitrogen than nitrogen being taken in

HS is associated with elevated levels of ____________; __________ release stimulates glucose / fatty acid metabolism

cortisol (glucocorticoid); cortisol

The resulting mobilization of protein, lipid and carbohydrate serves to

maintain normal tissue function in the presence of limited dietary intake, as well as to support the requirements of the immune response and wound healing

Cells of the immune system receive top priority in terms of utilization of________ ________

amino acids (released from muscle)

Glutamine is taken up by liver, immune cells:

serves as a nitrogen donor for purine nucelotide synthesis

Fatty acids are mobilized from adipose to provide alternative fuels and to spare ________.

glucose

Fatty acids become major source of fuel for muscle under these conditions

Starvation vs HS

Starvation- decreased metabolic rate

HS- increased metabolic rate (this may help drive repair and drive immune system)

HS is characterized by __________ nitrogen balance; protein breakdown and nitrogen excretion are ________ than dietary protein intake.

negative; greater

Amino acids are directed toward building ____________ ______________ ____________ to promote recovery

immune system proteins

Amino acids are important for

building proteins, cellular energy, and providing raw material for synthesis of neurotransmitters, hormones, and nucleotides.

Metabolism of amino acids can generate ___________, which is packaged into urea via the Urea cycle.

ammonium

Vitamin B12 and folate (vitamin B9) are both important cofactors in ____________ ____________, which is critical for production of blood cells and other dividing cells.

nucleotide biosynthesis

Several amino acids are __________ of important neurotransmitters

precursors

Purine and pyrimidine synthesis involves raw materials from several key ________ ________ __________

amino acid precursors

Disruption of amino acid metabolism can lead to

accumulation of toxic molecules, resulting in disease

Physical trauma or critical illness results in a _________ _________, in which amino acid metabolism is altered to drive immune cell production and fight infection

hypercatabolic state