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Flashcards in Protein Biochemistry Deck (72)
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31

What would a build-up of alpha-keto acids in teh body indicate?

a problem in the metabolism of branched chain amino acids can lead to a rise in alpha-keto acid concentration
♣ Maple Syrup Urine Disease (MSUD) occurs when this dehydrogenase complex is deficient and there is consequently a build up of the a-keto acids in urine (“sweet smelling”).

32

Tyrosine is an important amino acid for the immune system. Why?

¬ Tyrosine is used to make T4 (prohormone) that is converted to T3 (hormone). - these are thyroid hormones
¬ Thyroid stimulating hormone (TSH): Stimulates iodide (I-) uptake and stimulates release of T4,T3.
♣ Thyroid peroxidase (enzyme): Oxidizes iodide (I-) to (I2).
♣ Thyroglobulin (Tg): Contains Tyr residues iodinated to form T4,T3.
♣ Thyroxin binding globulin (TBG): Transports T4,T3.

33

Heme is synthesized by the production of porphyrin rings. How is this process accomplished?

¬ To produce a porphyrin the following reactions take place:
1. Gly + succinyl CoA --> alpha-Aminolevulinic acid (ALA) (catalyzed by alpha-Aminolevulinate synthase)
2. 2x ALA --> Porphobilinogen (catalyzed by by alpha-Aminolevulinate dehydratase)
3. Porphobilinogen --> Protoporphyrin IV (catalyzed by 4 enzymes)
4. Protoporphyrin IX --> Heme (catalyzed by Ferrochelatase)

34

Lead poisoning can lead to a porphyria. What is this and why does Lead mess with porphyrin?

¬ Porphyrias are the general term for diseases in porphyrin synthesis.
¬ Lead inhibits two enzymes in porphyrin synthesis (alpha-Aminolevulinate dehydratase, AND ferrochelatase)

35

Describe how porphyrin is broken down

¬ Porphyrin (Heme) degradation:
♣ Reactions Heme --> biliverdin (green) --> bilirubin (red-orange), -->bilirubin diglucuronide --> urobilinogen --> stercobilin (brown)
♣ Bilirubin is transported in blood via albumin.
♣ In liver, bilirubin is conjugated with glucuronic acid --> bilirubin diglucuronide (or otherwise known as conjugated bilirubin).
♣ In intestine, bilirubin diglucuronide is oxidized --> stercobilin.
♣ Jaundice occurs when bilirubin cannot be processed properly (i.e. hemolytic jaundice occurs when too many RBCs lyse, neonatal jaundice when bilirubin diglucuronide is not produced fast enough by low levels of bilirubin glycuronyltransferase).

36

Which amino acids contain sulfur?

Met and Cys comprise the two sulfer-containing amino acids

37

What is super important about cysteine?

¬ Cysteine (an unessential amino acid) is unique in that the –SH can form disulfides with another Cys, which is important for the structural integrity of many proteins (especially extracellular proteins).
♣ Glutathione (GSH): tripeptide that controls redox potential via GSH GSSG, where cysteine is the central amino acid that actually does the work here.

38

what is important about methionine?

¬ Methionine (an essential amino acid) is unique in that it is used to produce S-adenosylmethionine, which is also an intermediate in the production of cysteine.
♣ S-adenosylmethionine (SAM): produced in the first step of methionine degradation and converted to S-adenoyslhomocysteine (SAH). SAM is major Carbon donor and a “high energy storage unit” like ATP.

39

If a patient's GI is messed up and if they have a weird diet, what important sulfur amino acid can they be deficient in?

Methionine is an essential amino acid

40

What is the process of methionine recycling?

¬ Recycling Met reactions: Met --> SAM --> SAH --> Homocysteine --> Met
♣ Homocysteine --> Met needs THF and Vit-B12 to transfer back CH3 group.

41

What is SAM?

S-adenosylmethionine (SAM): produced in the first step of methionine degradation and converted to S-adenoyslhomocysteine (SAH). SAM is major Carbon donor and a “high energy storage unit” like ATP.

42

Methionine can be made into cysteine how?

¬ Met --> SAM --> SAH --> Homocysteine --> Cystathionine --> Cysteine

43

What are the three diseases of sulfur-containing amino acids that we need to know about it?

¬ Hyperhomocysteinemia:
*Homocystinuria
*Cysteinuria

44

Describe what's going on in the three sulfur amino acid disorders we need to know

¬ Hyperhomocysteinemia: elevated levels of homocysteine cause multiple problems that include cardiovascular disease. Results from low levels of folate, B6, & B12 (vascular disease). Cysteine is now essential and treat with folate, B6, & B12. - this will drive the reaction toward the production of methionine from homocysteine and reduce the homocysteine levels

*Homocystinuria: results from defect in cystathionine-b-synthase (CBS) and cannot convert homocysteine to cystathionine (and eventually cysteine). Leads to mental retardation, osteoporosis, & vascular disease. Cysteine is now essential. Can treat with Vit B6 to “force” CBS activity.

*Cysteinuria : kidney stones (renal failure), due to defective in transporter of cysteine (& Ornithine, Lysine, Arginine) that leads to crystallization in urea, treat with acetazolamide that makes cysteine more soluble.

45

What is up with hyperhomocysteinemia?

¬ Hyperhomocysteinemia: elevated levels of homocysteine cause multiple problems that include cardiovascular disease. Results from low levels of folate, B6, & B12 (vascular disease). Cysteine is now essential and treat with folate, B6, & B12.

46

what is up with homocystinuria?

*Homocystinuria: results from defect in cystathionine-b-synthase (CBS) and cannot convert homocysteine to cystathionine (and eventually cysteine). Leads to mental retardation, osteoporosis, & vascular disease. Cysteine is now essential. Can treat with Vit B6 to “force” CBS activity.

47

what is up with cysteinuria?

*Cysteinuria : kidney stones (renal failure), due to defective in transporter of cysteine (& Ornithine, Lysine, Arginine) that leads to crystallization in urea, treat with acetazolamide that makes cysteine more soluble.

48

What cofactors and amino acids are highly utilized to transfer carbon atoms?

Several cofactors are used for transferring carbons (Fig 3):
¬ SAM - high energy metabolite and carbon donor
*Tetrahydrofolate (THF) is synthesized in bacteria and its precursor, folate, is a vitamin for mammals. The one-carbon group, in any of three oxidation states, is bonded to N-5 or N-10 or to both.
*we should recognize that this carbon can be in several different states of oxidation, and might need to be "regenerated" before it can be added to another skelaton
*The most reduced form of the cofactor carries a methyl group, a more oxidized form carries a methylene group, and the most oxidized forms carry a methenyl, formyl, or formimino group.
*The different forms of tetrahydrofolate are interconvertible and serve as donors of one-carbon units in a variety of biosynthetic reactions

49

Glutathione is super important for the cell why?

*main importance = protection from reactive oxygen species
*¥ GSH is a highly soluble tripeptide as opposed to Cys.
¥ As high as millimolar in some tissues.
¥ Functions:
i) thiol acts as redox buffer (“SH buffer”) to maintain proteins in their reduced forms (i.e. intracellular proteins) and regulate activity (i.e. enzymes)
ii) Cofactor for several enzymes (i.e. Glutathione transferase, GST).
iii) Reduce hydrogen peroxide (H2O2) to water and general protection against ROS (radical oxidizing species).

50

you see ORNT1 and ORNT2 and you think what?

the antiporters will transport ornithine in (mitochondria), citrulline is transported out (to cytoplasm)
*important to fuel the first step of the urea cycle (formation of carbamoyl phosphate)

51

While CPS-1 might be the more important control point for protein catabolism, what is the first control point?

the first control point for protein catabolism is the relative concentrations of substrates and reactants
*in particular, the substrate concentrations that dictate teh directionality of the aminotransferases

52

Glutamate can be produced from what other amino acid that can cross the BBB?

glutamine can be made into glutamate, and this is super important for nerve tissue (glutamatergic neurons)

53

you see Glu Dehydrogenase and you think....?

*important control point for urea cycle and for protein catabolism
*also, think FREE AMMONIA (can go both ways, either shuttling or removing the ammonia) - thus the relative substrate concentrations will dictate the directionality of these reactions
*glutamate --> alpha-ketoglutarate is an example of freeing ammonia
*this particular reaction is regulated by ATP/ADP ratios
*inhibited by high energy state, stimulated by low energy state
*this enzyme, when mutated, can result in hyperinsulinemia????

54

what are the amino acids that are both ketogenic AND glucogenic?

tyrosine, valine, isoleucine, leucine (branched chain plus tyrosine)

55

What is thyroglobulin (tg?)

*important for the production of thyroxine
This is a giant protein complex that has 140 tyrosines, only a couple of which are iodinated
*T3 and T4 come off of this large complex through protealysis
*transferred to thyroxine binding protein for shuttling through the blood
*think of this as the sacrificial goat, which is destroyed to release the hormones T3 and T4

56

ALAS1 and ALAS2 are inhibited by what?

*their end products, there is feedback inhibition in heme synthesis
*lead will act like a constant presence of heme production feedback-inhibition

57

what is important about tryptophan metabolism?

¬ Trp is metabolized to pyruvate or acetyl-CoA. (ENERGY) - glucogenic
¬ Trp is first hyroxylated by tryptophan hydroxylase using tetrahydrobiopterin (BH4) as a cofactor
¬ Trp is used to produce serotonin (neurotransmitter), melatonin (hormone), and niacin (energy).

58

What neuronal complications can result from a problem in tryptophan handling?

¬ Trp is used to produce serotonin (neurotransmitter), melatonin (hormone), and niacin (energy).
¬ BH4 deficiency - Trp is first hyroxylated by tryptophan hydroxylase using tetrahydrobiopterin (BH4) as a cofactor
*symptoms = affected patients typically have hyperphenylalaninemia (HPA) and/or progressive neurologic deterioration during infancy due to decreased production of the neurotransmitters dopamine, epinephrine, norepinephrine, and serotonin
*Untreated patients typically die before reaching one year of age

59

What is important about Phe and Tyr metabolism?

¬ Phe, Tyr are metabolized to fumerate or acetoacetate. (ketogenic AND glucogenic)
¬ Phe is hydroxylated by phenylalanine hydroxylase to produce Tyr using BH4 cofactor (so can be a problem in PKU and BH4 deficiency) - so it's one pathway, just one extra step for Phe to make Tyr
¬ Tyr is hydroxylated by tyrosine hydroxylase to produce DOPA using BH4, which is subsequently metabolized to:
♣ Catecholamines, which include DOPA, dopamine, norepinephrine, epinephrine.
♣ Melanin, which is a pigment produced as a complex combination of several molecules derived from Tyrosine metabolism.
¬ Metabolic diseases in Tyr metabolism include:
♣ Phenylketonuria (PKU), which is a defect in phenylalanine hydroxylase that leads to build-up of alternative byproducts (phenyllactate, phenylacetate, and phenylpyruvate).
♣ Tyrosinemias are defects in the mutli-step tyrosine degradation categorized as types I, II, and III that refer to the particular dysfunctional enzyme involved.

60

What are the metabolic diseases in Tyr metabolism that we are expected to know?

¬ Metabolic diseases in Tyr metabolism include:
♣ Phenylketonuria (PKU), which is a defect in phenylalanine hydroxylase that leads to build-up of alternative byproducts (phenyllactate, phenylacetate, and phenylpyruvate).
♣ Tyrosinemias are defects in the mutli-step tyrosine degradation categorized as types I, II, and III that refer to the particular dysfunctional enzyme involved.