M2C Unit 3 Diseases

What are the ketogenic amino acids?

Leucine and Lysine (only)

What amino acids are both ketogenic and glucogeni?

Phenylalanin, Tyrosine, Tryptophan, Threonine, Isoleucine

Where does NH3 come from in the Urea cycle?

glutamine

What organ is urea produced in?

liver

What is the source of the two amine groups in urea?

glutamic acid and aspartic acid

NAG synthase is upregulated by what?

Arginine

N-acetyl glutamate or NAG activates what enzyme?

Carbamoyl Phosphate Synthetase I (CPS-I)

Which CPS enzyme uses Glutamine?

CPS-II

Overall reaction of Urea Cycle

NH3 + CO2 + Aspartate → Urea + fumerate

hyperammonemia

Extensive ammonia accumulation leads to extensive liver damage and death. Liver cirrhosis caused by alcoholism creates an interference in the enzymes which produce carbamyl phosphate in the first step on the cycle.

hyperammonemia -1

defective CPS-I so

ammonia accumulates

hyperammonemia-2

defective ornithine transcarbomylase so

ammonia accumulates

Citrullinemia

defective Arginini succinate Synthase

Citrulline accumulates

Arginosuccinic aciduria

defective Argininosuccinate lyase

Arginosuccinate accumulates

Argininemia

defectice Arginase

arginine accumulates

NAG Synthase deficiency

CPS-I does not activate = no urea cycle = high nitrogen = low BUN

Ornithine Trnsporter Deficiency

Ornithine accumulates in the cytoplasm and is unable to enter the mitochondria

HHH syndrome

Hyper ornithinemia, Hyperammonemia, Homocitrillinuria = low BUN

HHH syndrome treatment

Intravenous administration of sodium benzoate, phenyllacetate which condence with glycine and glutamate to form easily secreted and water soluble products

low BUN levels

Liver dysfunction

high BUN levels

Kidney dysfunction

B1

Thaimine (TPP)

B2

riboflavin (FAD)

B3

Niacin (NAD)

B5

Pantothenic Acid (CoA)

B6

Pyridoxine Phosphate (PLP)

B7

Biotin

B9

Folate

B12

Cobalamin

DHFR inhibitor

Methotrexate (MTX)

Thymidylate Synthase inhibitor

5- Flourouracil (5-FU)

MTHFR inhibitor

DHF and SAM

MS (Methionine Synthase)/ Homocysteine methyl transferase cofactor

B12

Serine Hydroxymethylene transferase (SHMT) cofactor

Pyridoxal phosphate (B6)

Homocystinuria symptoms

• Deep vain thrombosis (DVT)

• Stroke

• Atherosclerosis

• Marfin-like habitus

• Mental retardation

• Joint contractures

Homocystinuria

disorder of methionine metabolism

very B6 high homocysteine

high methionine (somtimes)

decreased cysteine

Cystathionine β-synthase deficiency = (low cystathione b/c homocysteine → cystathionine is reduced)

B6 deficiency

B12 deficiency

folate (B9) deficiency

Homocystinuria

Marfanoid habitus + thrombosis

Homocystinuria

Megaloblastic anemia

macrocytic anemia caused by impaired DNA synthesis

B12 (cobalamin)/B9(folate) deficiency

No dUMP → dTMP

high homocysteine

high methylmalonic acid (b/c low B12)

Megaloblastic anemia

Megaloblastic anemia symptoms

megaloblasts (large immature RBC precursors)

anemia

B12 (cobalamin) decificncy

• high homocysteine

• high methylmalonic acid

B12 (cobalamin) decificncy symptoms

• Megaloblastic amenia

• nerve damage

• painful and swollen tongue

• pernicious anemia

B9 (Folate) deficiency symptoms

• Spina bifada

• anencephaly (neural tube defect)

• macrocytic anemia

B9 (Folate) deficiency

high homocysteine

normal methylmalonic acid

Purine ring atom sources

Glycine

CO2

Asparate

Glutamine

10-Formyl THF

PRPP (ribose sugar synthesis) committed step

glutamine and water to 5'-phosphoribosylamine (PRA), glutamate, and pyrophosphate - catalyzed by amidophosphoribosyltransferase

amidophosphoribosyltransferase activator

PRPP

amidophosphoribosyltransferase inhibitor

AMP, GMP, IMP

IMP to AMP requires the addition and removal of what?

Aspartate in and fumerate out

IMP to GMP requires the addition and removal of what?

Glutamine in, Glutamate out

XMP is converted to what?

GMP

PRPP is the donor of what group?

5-phosphoribosyl group

Catabolized Purines are converted to what?

uric acid

HGPRT deficiency (Lesch-Nyhan syndrome)

•Spastic cerebral palsy

•Self-mutilation (hands, lips)

•Hyperuricemia

•Early death

Adenosine deaminase (ADA) deficiency

•Severe combined immunodeficiency

•Low T- and B-cells => infections

• Autosomal recessive

Purine Salvage Excretion pathway final product

Uric acid

Purine-nucleoside phosphorylase (PNP) role

separates the free purine base from the ribose (or deoxyribose)

Excessive Sodium urate results in

Gout (excess uric acid)

deficiency of hypoxanthine-guanine phosphoribosyltransferase or defective regulation of purine biosynthesis can result in?

Gout (excess uric acid)

Allopurinol is a treatment for

gout (lowers uric acid)

Allopurinol is an inhibitor for what enzyme?

xanthine oxidase

azathioprine

Purine Syntheiss inhibitor

• immunosuppressant used in organ transplantation, autoimmune disease such as rheumatoid arthritis or inflammatory bowel disease such as Crohn's disease and ulcerative colitis.

Mycophenolate mofetil

inhibits purine synthesis by blocking inositol monophosphate dehydrogenase

Methotrexate

indirectly inhibits purine synthesis by blocking the metabolism of folic acid (inhibits dihydrofolate reductase)

Cholchicine

reduces inflammation, has no effect on uric acid production. Reduces macrophage ingestion of uric acid crystals.

Probenecid and sulfinpyrazone

increase uric acid excretion

Pyrimidine ring atom sources

Glutamine

Aspartate

HCO3-

Adenosine Deaminase is the enzyme used to convert what to what?

Adenosine → Insosine

Purine nucleoside phosphorylase (PNP) yields what two products?

Hypoxanthine and Guanine

In purine salvage pathway, what inhibits amidotransferase?

6-mercaptopurine

“Mercaptopurine murders purines” → inhibits: de novo purine synthesis

Role of amidotransferase?

Increases de novo purine synthesis

If Salvage pathway HGPRT (HPRT) if deficient or inhibited, you get?

Lesch-Nyhan syndrome

defective Glucose-6-phosphatase

Von Gierke disease

defective Lysosomal acid α-1,4-glucosidase

Pompe disease

defective Debranching enzyme

Cori disease

defective Branching enzyme

Anderson Disease

defective Muscle glycogen phosphorylase

McArdle disease

defective Liver glycogen phosphorylase

Hers disease

What process is Carbamoyl Phosphate II (CPS-II) a part of?

Pyrimidine Synthesis

Mitochondrial CPS I uses what as nitrogen source

NH3

Cytosolic CPS II uses what as the nitrogen donor to carbamoyl phosphate

glutamine

CPS-II activators

PRPP and IMP

Aspartate transcarbamoylase (ATCase)

Catalyzes the first committed pathway step for pyrimidine synthesis

In pyrimidine synthesis, if PRPP OR UMP synthase are defective what happens?

Orotic Aciduria = high orotic acid (only)

If Ornithine transcarboxylase (OTC deficiency) in Urea cycle is inhibited, what happens?

high orotic acid = orotic aciduria

high carbamoyl phosphate in mitochondria

defective or inhibited Ribonucleotide reductase (UDP → dUDP + CT))

hydroxyurea

Trimethoprim inhibits?

DHFR

Pyrimethamine inhibits?

DHFR

Inhibited Phenylalanine Hydroxylase or low tetrahydropteridin

Phenylketonuria (PKU) = high Phenylketones

•Mental retardation

•Musty odor in urine

•Microcephaly

•Avoid aspartame

•Diet low in Phe

Phenylketonuria, PKU

defective or inhibited Tyrosinase = low Melanogenesis

Albinism

•Dark urine

•Ochronosis

•Arthritis

• urine turns black or dark on standing

• bluish-black connective tissue pigmentation (bluish/blackish tips of ear)

Alkaptonuria

homogentisate oxidase deficiency = high homogentisic acid

Alkaptonuria

brankched chain ketoacid dehydrogenase

Maple Syrup Urine Disease

•Urine has odor of maple syrup

•Color is caramel

•Abnormal muscle tone

•Mental retardation

•Ketosis

•Coma, Death

Maple Syrup Urine Disease

• No or low B12

• defective Methylmalonyl-CoA mutase

• high Methylmalonate

Methylmalonic aciduria

• Low/No Biotin

• Propionyl-CoA Carboxylase is defective

high propionyl-CoA

Homocystinuria = high homocysteine

defective Homocysteine methyl transferase

Homocystinuria = high homocysteine

defective Cystathionine synthase and little to no B6