MSK 1.1 Midterm

what is the protein path for nitrogen metabolism?

ingested —> stomach + SI —> skeletal muscle —> liver —> kidney —> excretion

what happens to nitrogen in the stomach + SI?

hydrolyzed to amino acids

how is nitrogen transferred from skeletal muscle —> liver?

• turned into alanine and glutamine via transamination + aminotransferase

• non- toxic ammonia carriers

what is alanine used for?

used by muscle to transfer nitrogen to liver

what is glutamine used for in AA metabolism?

transfers nitrogen to liver for excretion

how is nitrogen sent from liver —> kidney?

urea cycle

how does hyperammonia occur?

• Ala or Glu can’t accept NH3 —> asterixis (hand flap)

• excess nitrogen NOT converted to urea

when does negative nitrogen balance occur?

• illness

• starvation: protein breakdown releases nitrogen —> excrete

enzyme markers for skeletal muscle damage

• AST + CK

• ALK PHOS, gamma-GT

enzyme markers for liver damage?

AST + ALT

enzyme markers for kidney damage?

BUN + creatine

skeletal muscle metabolism: Arg Path

Arg + Gly —> creatine —> ADP + creatine-Phos —> ATP + creatine

what does creatine kinase do?

• ADP + creatine-Phos —> ATP + creatine

• reversible

what is function of creatine?

• made in kidney

• storage fuel in muscle

what are the 4 sources of energy produced by Arg path?

• ATP (1-2 sec)

• phosphocreatine transfers phosphate —> ADP

• glycolysis (1 min), anaerobic

• ox phos (hrs), aerobic

skeletal muscle metabolism: NO path

• uses cGMP signal —> EDRF (NO)

what does EDRF (NO) signal for cGMP result in?

• smooth muscle relaxant —> stops myosin

• vasodilation: dec Ca2+ —> dec BP

• NT uses phosphodiesterase to hydrolyze cGMP

• dec blood coagulation + phagocytosis

BCAA pathways characteristics

• catabolized in skeletal muscle

• can’t be direct substrate for beta oxidation

Ile + Val path

Ile or Val or allo-Ile —> long ketoacid —> shorter ketoacid —> PPC —> MMC —> succinyl coa

what does transamination do?

• starting substrate —> long ketoacid

• glutamine carries amine to urea cycle

what does BC ketoacid dehydrogenase do in the Ile + Val + allo-Ile path?

• cofactor B1

• long ketoacid —> shorter ketoacid

Maple Syrup Urine Disease

• defective BC ketoacid dehydrogenase + B1 (both BCAA paths)

• labs: BCAA, allo- Ile

• symptoms: cerebral edema, sweet urine, ketosis, hypotonia

what is the function of the 2 carbon removal?

• shorter ketoacid —> propionyl coa (organic acid)

• isovaleric acid —> shorter skeleton (also IVD)

• like beta ox

what is the function of propionyl coa carboxylase?

• cofactor B7

• propionyl coa —> MM coa

MM CoA Acidemia

• defective MMC mutase + B12

• labs: MMC acid + ketone in blood + urine, hyperammonia + ketoacidosis

• symptoms: hypotonia, hepatomegaly, thrombocytopenia, renal/heart failure

BCAA path: Leu

• only converted to ketogenic substrates

• Leu —> long ketoacid —> isovaleric coa —> shorter skeleton —> acetoacetate

what is the function of transamination?

• Leu —> long ketoacid

• NH3 side product —> urea cycle via Glu

what is the function of BC ketoacid dehydrogenase?

• long KA —> shorter KA (B1)

• long KA —> isovaleric acid (organic acid)

Isovaleric Acidemia

• deficiency in isovaleric dehydrogenase

• labs: isovaleric acid /coa in blood + urine

• symptoms: vomit, sweaty feet odor, lethargy, poor feeding

propionyl coa carboxylase deficiency

• more severe than isovaleric acidemia

• deficiency in PCC + B7

• labs: propionic acid + ketones in urine

• symptoms: dec VOMIT, encephalopathy, infection, cardiomyopathy

what does VOMIT stand for in PCC deficiency?

dec Val, OCFA, Met, Ile, Thr

BCAA path: Met + Cys

• Ala, Gly, Ser, Thr

• catabolic —> Met

• anabolic —> B12, B9

BCFA Met + Cys: catabolic pathway

• Met —> SAM —> homocysteine-SH —> cysthionine

• makes both propionyl coa + cys-SH

what does SAM produce?

phospholipids, DNA, NT

what does cysthionine beta synthase do?

• cofactor B6

• uses Ser-OH

• homocysteine-SH —> cysthionine

cysthionine products

• cofactor B6 —> Cys-SH

• propionyl coa

anabolic: B12 cycle

• transfers 1 carbon unit

• homocysteine —> Met via Met synthase +B12-CH3

• MM coa —> succinyl coa via MM coa mutase

deficiency in B12

• pernicious anemia, paresthesia, ataxia, memory loss

• inc MM acid, inc homocysteine

anabolic: B9 cycle

folate —> FH2 —> FH4 —> FH4 methylene —> FH4-CH3 —> FH

what does a folate deficiency cause?

dec DNA synthesis —> macrocytic anemia

what does the de novo purine synthesis pathway require?

aspartate, glutamine, CO2, glycine, THF

what is the de novo purine synthesis pathway?

ribose 5-P —> PRPP —> PRA —> IMP —> ATP + GTP

what is the starting substrate for de novo purine synthesis?

ribose 5-P from the HMP shunt in glycolysis

what does PRPP synthase do?

ribose 5-P —> PRPP

what inhibits PRPP and PRA?

AMP, GMP, IMP

what does IMP dehydrogenase do?

• PRA —> IMP

• NADH —> NAD

• inhibited by GMP

what does 6-MP and azathioprine do?

• inhibits GAPT

• dec nucleotide syn —> dec lymphocytes

characteristics of IMP?

• adenine + guanine intermediate

• made of hypoxanthine + PRPP

• inhibited by AMP product

what medication inhibits IMP —> GMP?

• mycophenolate: reversible, blocks guanine syn

• ribavirine: competitive, blocks purine syn

carbon sources for purine de novo

CO2, FH4, glycine

nitrogen sources for de novo

aspartate, glutamine, glycine

what does the purine salvage pathway do with bases?

adenine, guanine, hypoxanthine —> AMP, GMP, IMP instead of breaking it down uric acid

what is the general path for the purine salvage pathway?

nucleic acids —> nucleotides —> nucleosides —> free bases

what is the function of HGPRT in the purine salvage pathway?

• guanine + PRPP —> GMP

• hypoxanthine + PRPP —> IMP

Lesch Niemann

• HGPRT deficiency —> purines —> inc uric acid

• symptoms: gout, self-mutilation, neuro issues, orange sand crystals in diaper

• treat w/ allopurinol + febuxostat

what is the function of APRT in the purine salvage pathway?

adenine + PRPP —> AMP —> adenosine

what does adenosine feed into in the purine salvage pathway?

adenosine —> inosine —> hypoxanthine —> xanthine

SCID

• adenosine deaminase deficiency

• inosine production blocked

• dysfxn B —> pneumo
  dysfxn T —> albicans

what are the symptoms of SCID?

• B cell dysfxn: pneumocystis jirovecci

• T cell dysfxn: candida albicans

cladribine

• treats adenosine deaminase deficiency

• treats hairy cell leukemia

• purine analog, combines into DNA —> breaks down

what is the de novo pyrimidine synthesis pathway?

glutamine —> carbomyl phosphate —> orotic acid—> UMP —> UDP —> dUDP —> dUMP —> dTMP

what does CPS2 do?

• in cytoplasm

• rate limiting

• glutamine + CO2 —> carbomyl phosphate

OTC deficiency

• urea cycle defect

• inc orotic acid + ammonia due to EXCESS substrate

• symptoms: encephalopathy

• treat w/ dialysis

Leflunomide

• inhibits carbomyl phosphate —> orotic acid

• reversible DMAR inhibition dihydroorate

what does UMP synthase do?

orotic acid —> UMP

orotic acidemia

• ump synthase deficiency

• inc orotic acid due to BUILD UP

• symptoms: B12 + B9 resistant megaloblastic anemia

• treat w/ uridine

what does ribonucleotide reductase do?

• UDP —> dUDP

• inhibited by dATP

• stimulated by ATP

hydroxyurea

• inhibits ribonucleotide reductase

• halts DNA replication + arrest in S phase

• treat sickle cell

what does thymidylate synthase do?

dUMP —> dTMP

S-Fluorouracil + capecitabine

• inhibits DNA syn —> blocks thymidylate synthase

• dUMP —> dTMP

what does FH2 reductase do?

• DHF —> THF

• produces methylene THF —> ensures dTMP (needed for DNA syn)

• offshoot from dUMP

Methotrexate, Trimethoprim, Pyrimethamine

• inhibits FH2 reductase

• competitive, displaced FH2

• dec dTMP + purine nucleotide

what does the pyrimidine salvage pathway generate?

recovered uracil + thymidine —> uridine + deoxythymidine

how is uracil turned into UTP?

• uracil —> uridine via phosphorylase

• uridine —> UMP via kinase

• UDP —> UTP

how is thymine turned into dTPP?

• thymine —> deoxythymidine via phosphorylase

• deoxythymidine —> dTMP via thymidine kinase

• dTMP —> dTDP —> dTPP

what is the general collagen synthesis pathway?

nucleus —> RER —> golgi —> EC space

what occurs in the RER during collagen synthesis?

• prolyl or lysyl hydroxylation (vit C dep.)

• glycosylation of lysine

• proline rearrange via prolyl peptide isomerase

• assemble procollagen triple helix

what happens in the golgi during collagen synthesis?

procollagen secured to cell surface

what happens in the ECM during collagen synthesis?

• procollagen peptidases cleave terminal pro peptides

• forms tropocollagen —> not mature

• collagen fibrils cross link by lysyl oxidase w/ Cu2+

what are the alpha helixes formed from?

• repeating Gly-X-Y

  • hydroxyproline + hydroxylysine

  • hydroxylated by prolyl hydroxylase + vit C

where is type 1 collagen found?

• bones, tendons, cornea

• skin, BV

where is type 2 collagen found?

cartilage, IV disc, vitreous humor

where is type 3 collagen found?

arteries in reticulum (skin + muscle), BV, wound repair

where is type 4 collagen found?

basement membrane

osteogenesis imperfecta

• defective COL1A1/2 (T1 collagen)

• Gly replaced with bulky side chain

• symptoms: blue sclera, recurrent fractures, hearing loss

ehler’s danlos (vascular)

• defective COL3A1 gene (T3 collagen)

• symptoms: thin skin, bruising, artery rupture, hollow organ

ehler’s danlos (classic)

• defective COL5A1/2 (T5)

• symptoms: hypermobility, cigarette paper scars

menkes

• defective ATPTA gene —> dec lysyl oxidase (cyt) + dec Cu

• symptoms: sparse, brittle hair, dec body temp, hypotonia, seizures

scurvy

• vit C def —> dec prolyl hydroxylase (RER)

  • ascorbate def also cause

• dec collagen strength, fragile BV, loss of teeth, petechiae

system sclerosis

• inc collagen production —> hardening of skin, other systems

• raynaud syndrome

what is elastin produced by?

• fibroblasts

• smooth muscle, endothelial cells, chondrocytes

what makes elastin flexible?

• ELN gene

• proline + lysine (elastic)

elastin structure

mesh, crosslinked by desmosine

elastic fiber relaxed

contracted —> less ordered —> inc entropy

elastic fiber stretched

expanded —> more ordered —> dec entropy

what does AAT normally do?

• inhibits elastase (protease)

• elastase can’t break down elastin

what occurs during emphysema?

• dec AAT —> elastase activated

• causes lung damage, alveolar wall breakdown

williams beuren

• partial del of Chr. 7 (elastin)

• elfin appearance, intellectual disability, aortic stenosis

marfan

• Chr. 15 (FBN1) Mut.

• tall/long, sunken chest, heart issues, lens issue

glycoprotein characteristics

• adhesive proteins

• proteoglycans + collagen linked together + cell surface via fibronectin or laminin