Protein Biochem 3

Question 1

Sulfur containing amino acids

Answer 1

Methionine (essential amino acid)
-used to produce S-adenosylmethionine(SAM), which is an intermediate in production of cysteine
SAM: produced in first step of methionine degradation and converted to SAH (S-adenosylhomocysteine)
-SAM is a major carbon donor and high energy storage unit like ATP

Cysteine: non-essential aa (synth from methionine) the -SH can form disulfides with another Cys (makes Cystine when two together)

• Disulfide cross links are critical for the stability of many proteins (outside cell many oxidized, inside many are reduced)
• Glutathione (GSH): tripeptide that controls redox potential via GSHGSSG– where cysteine is the essentail aa that does the work

Question 2

Recycling Met rxns

Answer 2

Met–> SAM–> SAH–> homocysteine–> Met
Homocysteine to met needs THF and Vit B12 to transfer back CH3 group (methyl group trans to THF to B12 to homocysteine)
-Met to SAM by ATP dependent SAM synthase
-SAM to SAH with methyltransferases

Met–> SAM–> SAH–> homocysteine–> cystathionine–> cysteine

• homocysteine combined with serine using CBS (cystathionine beta-synthase)
• glucogenic
• cystathionine to cyteine using cystathionine gamma-lyase
• use of PLP (Vit B6) for both enz

Question 3

Hyperhomocysteinemia

Answer 3

elevated levels of homocysteine

• multiple problems including CV disease
• results from low levels of folate, B6, B12 (vascular disease)
• Cysteine is now essential and treat with folate, B6, and B12
• vascular disease
• impaired wound healing
• correlated to cancer (cervical cancer)

Question 4

Homocystinuria

Answer 4

• results from defect in cystathionine-b-synthase and cannot convert homocysteine to cystathionine (and eventually cysteine).
• Leads to MR, osteoporosis, vascular disease
• Cysteine is now essential
• can treat w/ B6 to “force” CBS activity

Question 5

Cysteinuria

Answer 5

• kidney stones (renal failure)
• defective in transporter of cysteine (and ornithine, lysine, arginine) that leads to crystallization in urea
• treat with acetazolamide that makes cysteine more soluble

Question 6

Cofactors used for transferring carbons

Answer 6

-SAM, donor of CH3 (high energy storage): serves many biological roles; can methylate norepi–> epi, can methylate cystosine residues in DNA

-THF (tetrahydrofolate): donor of CH3, CH2, CH=NH (formimino), CH=O (formyl): synth in bacteria, or precursor is folate vitamin:
the one carbon group is bonded to N-5, N-10 or both
the most reduced form carries methyl group
more oxidized carries methylene group
most oxidized carries methenyl, formyl, or formimino group
Different forms of THF are interconvertible, serve as donors of one carbon units
-THF is produced from Vit B9 (folic acid) by dihydrofolate reductase (DHFR)
-THF is essential for synthesis of aa and nuclei acids
-methotrexate can block enz DHFR

Question 7

Glutathione (GSH)

Answer 7

-GSH (from glutamate, cysteine, and glycine) is a highly soluble tripeptide (as opposed to cysteine)
Functions:
-thiol acts as a redox buffer (“SH buffer”) to maintain proteins in their reduced form (intracell prot) and regulate activity (Enz)
-Cofactor for several enz (glutathione transferase, GST)
-Reduce hydrogen peroxide (H2O2) to water and general protection against ROS

Question 8

Trp metabolism (aromatic)

Answer 8

• Trp is metabolized to pyruvate or acteyl-CoA.
• Trp is first hydroxylated by tryptophan hydroxylase using tetrahydrobiopterin (BH4) as a cofactor.
• Trp is used to produce serotonin, melatonin, and niacin (for vit b3, energy, NAD)

-ketogenic (many steps) and glucogenic (serotonin, melatonin, Niacin)

Question 9

Phe and Tyr metabolism (aromatic)

Answer 9

-Phe and Tyr are metabolized to fumarate or acetoacetate
-Phe is hydroxylated by phenylalanine hydroxylase to produce Tyr using BH4 cofactor
-Tyr is hydroxylated by tryosine hydroxylase to produce DOPA using BH4, which is metabolized to:
Catecholamines (DOPA, dopamine, epi, norepi)
Melanin (pigment produced as complex combo of several molecules derived from tyrosine metabolism

Question 10

Phenylketonuria

Answer 10

• defect in phenylalanine hydroxylase that leads to build-up of alternative byproducts (phenyllactate, phenylacetate, and pheylpyruvate)
• Phenylacetate has a distinct smell which you can smell in urine, where excreted

Question 11

Tyrosinemias

Answer 11

-defects in the multi-step tyrosine degradation categorized as types I, II, II that refer to the particular dysfunctional enzyme involved.

Question 12

BH4 as cofactor

Answer 12

• Phenylalanine hydroxylase
• tyrosine hydroxylase
• tryptophan hydroxylase

Question 13

GSH and RBCs

Answer 13

• GSH is imp for RBCs (hemoglobin)
• the heme iron must be ferrous (Fe2+) to bind O2
• Oxidation of heme, ferrous (Fe2+) to Ferric (Fe3+) cannot bind oxygen
• GSH can keep the heme reduced for functional hemoglobin

Question 14

Enzymes related to GSH

Answer 14

-glutathione peroxidase: oxidizes GSH to GSSG (mutations lead to higher breast cancer risk)

Glutathione reductase: reduces GSSG to GSH (mutations are rare, but esp problematic for RBCs (heme))

Glutathione-S- transferase: conjugation of GSH to agents (detox (ROS), drug resistance, upregulated in tumors (isoform piGST)

Question 15

Catecholamines

Answer 15

• NTs produces from Tyr

- cathechol and amine group

Question 16

Parkinson’s

Answer 16

• degenerative disorder of CNS
• loss of neurons–> low DA–> parkinson’s

Tx:

• DOPA
• MAOIs (prevent deamination and get buildup of intermediates)
• catecholamine Mehtylranferase inhibitors