UVM NMGI 1 Amino Acids

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1

Amino Acid parts

Amino Group+ (at physiological pH)
Carboxylic Acid - (at physiological pH)
Hydrogen Atom
Side Chain

2

AAs special because

Nitrogen
Building blocks of prot
No designated storage

3

AA input

Prot breakdown 400 g/d
Diet 100 g/d
synth variable

4

AA outflow

Body prot synth 400 g/d
Synth N compounds 30 g/d
Buring AAs as fuel variable

5

Excess AA

degraded and nitrogen excreted as urea

6

Neg N balance

Starvation= AA catabolized for gluconeogenesis, N elim and not reincorp

Diesease= essential aas scavanged

7

Pos N balance

Growth: more AA incorp than catabolized Arg and Cys essential under these conditions

Pregnancy

Recovery from starvation

8

Fast turnover prot

minutes
Cell signaling, reg enzymes, hormonal signals, misfolded

9

Med turnover prot

hours-days
Enzymes, lipoprot

10

Slow turnover prot

days-weeks
structural= myofibrillar: myosin and actin
CT: collagen

11

Protein Degradation systems

Lysosomes
Ubiquitin proteasome system

12

Lysosomes

acidic organelles, degrade prot non-selectively in well nourished cells

13

Method of entering lysosomal path

Endocytosis= from ER
Cytosolic encapsulation= vacuoles in cytosol

14

Prolonged fasting

proteins w/ specific aa seq are degraded by lysosomes

Selective loss of prot from tissues that atrophy in response to fasting: liver and kidney. Not from brian and testes

DM, muscle atrophy, denervation, regression of uterus after childbirth

15

Ubiquitin/ proteasome system

specialized set of cytoplasmic prot, which can detect incorrectly assembled prot. and direct them to sites for proteolysis

16

Ubiquitin

Ubiquitin + ATP-> UbqE1-> UbqE2-> UbqE3-> Protein substrate: misfolded or phosphorylated-> ubiquinated prot goe to proteasome

17

E1 reg spec

1 or 2

18

E2 reg spec

10-15

19

E3 reg spec

100s= determines which prot are ubiquinated, can be structurally unrelated

20

E3 enzyme ubiquitin ligase

targets proteins
-uses N terminal rule
-PEST sequences: Pro-Glu-Ser-Thr
-Cyclin destruction boxes

21

Bortezomib : Velcade

a proteasome inhibitor

used to tx mult myeloma, also can be used for hematologic CAs and solid tumors

Side effects peripheral neuropathy, myelosupression as neutropenia, and thrombocytopenia

22

Final digestion of peptides

Endopeptidases
dipeptidases
aminopeptidases

Specific transporters are present on the intestinal cells to take up AAs and the smallest peptides

23

AA transport

AA transport ATP driven sodium dependent and sodium independent

24

Sodium dependent AA transport

FAst response
AAs with high intracellular gradients

25

In well fed state

Glucose AAs, and fat are supplied by food

AAs reach liver and are used for prot synth-> to make plasma prot, passed to other tissues for prot synth at those sites, converted to metabolic intermediates for FA synth w/ release of N

Most AAs pass through w/out processing, important for essential AAs

No gluconeogeneis or Cori cycle

26

Glutamine=

50% of all circulating AAs

27

Alanine=

25% of all circulating AAs

28

Glutamine Shuttle

Carries 2 N groups

Sequestering Ammonia to glutamine requires ATP, and is catalyzed by glutaminase

29

Nitrogen transport

Muscle
Kidney
Intestine

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Muscle makes

Gln-> Kidney
Ala-> Liver
and receives BCAA from the liver

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Intestin makes

All AAs from diet-> to liver
Gln-> Ala and citrulline-> to liver

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Kidney makes

Citrulline from liver into Arg
makes glucose and ammonia
Gln from muscle

33

Liver makes

citrulline to send to kidneys
Urea
Glucose
BCAA to send to Muscle

Recieves Ala from muscle, and all AA, ala, and citrulline from intestine

34

In early fasting

Hepatic glycogen uses to maintain blood glucose up to 8-12 hours

Cori cycle active, pyruvate and lactate are used to support the formation of glucose

Alanine cycle active where carbon and nitrogen atoms from muscle are returned to liver in exchange for glucose

35

Glucose Alanine cycle

Glucose from liver gluconeogensis-> muscle-> muscle glycolysis-> pyruvate-> BCAA from liver use carbon skeletons for cellular respiration and the NH4+ adds to pyruvate to form Alanine.-> alanine is sent back to liver-> in liver NH4+ is sent to glutamate and pyruvate is formed for gluconeogensis.

the NH4+ from glutamate is sent to the urea cycle.

36

In fasting state

no fuel is available in the gut
body is dependent on hepatic gluconeogenesis from cori cycle, alanine cycle, glycerol

Since fats cannot supply net glucose, it is obtained from AAs

muscle prot hydrolyzed and most aas converted to pyruvate and alpha ketoglutarate. yielding alanine and glutamine in largest amounts

BCAAs are major sources of the N for alanine and glutamine production in muscle

37

Glutaminolysis

involves gln conversion into lactate as source of energy in rapidly dividing cells ie enterocytes, tumors etc

38

during Cachexia

liver is removing AAs from plasma, promoting muscle hydrolysis

high glucagon increases liver AA utilization

During acidosis, liver bypasses ureas cycle: conserving bicarb by sending glutamine to kidney to be acted on by glutaminase

39

Nitrogen transport

N to liver + kidneys as AAs

In liver Glutaminase takes Glutamine to Glutamate

also ALT takes Alanin to Glutamine

40

AAs make

intact for biosynth
or carbon skeletons and animo groups -> need N disposal

41

Keto acids are the carbon skeletons of AAs

Pyruvate is the keto acid of alanine

42

AAs most important for metabolism

Glutamate= aa equiv fo alpha ketoglutarate, collects N from alanine, source of N for Urea cycle

Aspartate= AA equiv of oxaloacetate, used by cells for nucleotide synth, source of N for urea cycle

Alanine= AA equive of pyruvate, simult transports ammonia and pyruvate from muscle

Glutamine= Major form of nitrogen transport between tissues, used by various cells for fuel and DNA synth: glutaminolysis. Storage form of ammonia, used in the kidneys to raise pH through ammonia release

43

AAs from diet or muscle used for

building prot
glucose, glycogne, FAs TCA

44

Aminotransferase or transaminase

moves ammonia from an AA to an alpha keto acid.

45

ALT Alanine aminotransferase

transfers alanine to pyruvate and changes alpha ketoglutarate to glutamate.

ALT first step to collect N from alanine in urea cycle

46

AST Aspartate aminotransferase

exeception in funnelling amino groups to glutamate

changes glutamate to alpha ketoglutarate, and oxaloacetate to aspartate

During AA catabolism, AST functions in synth of aspartate -> urea cycle

47

ALT and AST needs

Vit B6 pyridoxine to form Pyridoxal Phosphate PLP prosthetic group

48

Hepatocellular Injury

Liver necrosis or apoptosis leads to elevated Serum ALT and AST

49

Elevated AST

Liver dis, cell disruption
indicates severe hepatic necrosis or ETOH hepatic disease if ratio >2 AST/ALT

50

Elevated ALT

Liver dis, cell disruption
viral hepatits, toxic injury ACUTE ratio <1AST/ALT

51

Why transaminate

getting rid of N, by making them into aspartate and glutamate

To ditch in the urea cycle

52

Glutamate dehydrogenase

makes NADH and releases NH3, combined into carbamoyl phosphate to enter TCA

done in mitochondria, can use either NAD+ or NADP+: not common

can be used in anabolic and catabolic pathways

53

Oxidative deamination

AA oxidized and ammonia is produced, while FMN, or NAD+ is reduced

54

Nonoxidative deamination

only applicable to hydroxyamino Acids :serine and threonine. the keto acid and ammonia are formed

55

Urea cycle

Ornithine enteres mito-> carbamoyl phosphate adds to it and creates citrulline-> citrulline enters cytoplasm-> adds aspartate and makes argininosuccinate-> Fumarate leaves and ARginine is left-> Arginine and water makes ORnithine and URea

56

2 steps in the TCA cycle

Fumarate to Malate to OAA

57

Ammonium ion/ Urea toxicity

increases pH to damaging levels
Inhibits oxidative phosphorylation
Interferes w/ redox balance

58

AA degradation

can be channeled to Acetyl CoA, Acetoacetyl CoA, pyruvate, alpha keto, succinyl CoA, fumarate, OAA

59

Ketogenic

destined to be burned up or made into ketone bodies, cannot be used for anabolism

Leucine and Lysine exclusively ketogenic will never net glucose

60

both gluco and ketogenic

Tyrosine, Isoleucine, Phenylalanine, tryptophan Aromatics plus Isoleucine

61

alanine

pyruvat

62

glutamate

alpha ketoglut

63

aspartate

OAA

64

Degradation of BCAAS

Leucine, isoleucine and valine= 1/3 of skeletal muscle, initiated in muscle so is unusual. before transamination, alpha keto BCAAs are oxidatively decarboxylated by branched chain alpha ketoacid dehydrogenaecom

65

Cysteine and Tyrosine

are conditionally essential AAs

Cysteine is derived from serine and requires sulfur derived from methionine

Tyrosine is derived from phenylalanine via hydroxylation

66

Arginine

is essential in growing animals that cannot obtain sufficient amounts from ornithine in the urea cycle.

67

Histidine and taurine are

semiessential AAs in children, because metabolic pathways to synthesize them are not fully developed

Taurine needed for formin bile salts, and has no carboxyl so is not technically an AA

68

PVT TIM HALL

Phenylalanine
Valine
Threonine
Tryptophan
Isoleucine
Methionine
Histidine
Arginine
Leuicine
Lysine

69

Why is an AA essentila

Higher ATP requirement for synth
Multi step synth
Diff enzymes for each step
Lots and lots of machinery and energy needed

Notable exception Proline= 39 ATP needed

70

Easily Synth AAs

Glutamate= transamin of alpha ketoglutarate
Glutamine= amination of glutamate by glutamine synthetase
Aspartate= Transamination of OAA
Asparagine= amination of aspartate by asparagine synthetase
Alanine= transamination of pyruvate

71

Involved biosynth

Proline and arginine = derived from glutamate
Serine and glycine= are obtained from glucose and glycerol

72

Conditionally essential

Sulf atom of cystein comes from methionine, w/ carbon skeleton from serine

Tyrosine is from hydroxylation of essential phenylalanine

73

Sulfer Amino Acids

Cysteine
Methionine
Homocysteine

74

Elevated Homocysteine levels

correlate w/ cardiovascular disease risk

75

S-Adenosylmethionine SAM

takes Methionine and ATP to S-Adenosyl homocysteine and adds an active methyl group-> add H20 to make homocysteine, add a methyl group to make-> methionine

76

Methionine Synthase

B12 requireing enzyme

Takes Homocysteine to methionine by adding a methyl group

Also takes N5 methyl THF to THF

77

Methylmalonyl CoA mutase

also requires B12 and gets propionyl CoA back into metab as succinyl CoA

78

The addition of methyl to THF

takes a methyl group from serine and forms glycine, and N5 methylTHF

79

Homocystein degradation

Condensation w/ serine via cystathionine synthase (PLP dep)-> cystathionine (then split cystathionine)-> cysteine and alpha keto butyrate and NH3 via cystathionase (PLP dep)

Alpha ketobutyrate-> propionyl CoA -> Succinyl CoA

without B6 = high homocysteine levels

80

Specialized products derived from AAs

Porphyrins
NTs
Purines and pyrimidines
Thyroxine
Phospholipids
Coenzymes
Hormones

81

Porphyrins two component

Glycine
Succinyl CoA

cyclin compounds that bind metal ions, makes pyrrole rings

82

Catecholamines

synth from tyrosine
Dopamine= NT in brain and ANS
Norepi- NT in brain and ANS synth in Adrenal medulla
Epi= methylated deriviative of norep, synth in adrenal medulla

83

Thyroxine t4 and t3 is triiodothryonine

synth from tyrosine, needs iodine

a form of thyroid hormone, secreted by follicular cells of the thyroid gland

84

Creatine

synth from
glycine
and guanidino group of arginine
along w/ a methyl group from SAM

Phosp form is found in muscle, can donate P to ATP. a small reserve can be mobilized very rapidly for energy

85

Creatinine

is a break down product of creatine phosphate in muscle, and is used as an indicator of renal function

86

Histamine

formed from histidine via histidine decarboxylase (requires B6, and is site of diphenhydramine hydrocholride action)-> histimine

87

Serotonin or 5HT

synth from tryptophan

numerous physiological roles, and is involved in the regulation of Px perception, affective disorders, sleep regulation, body temp, BP

88

Melanin

synth from tyrosine

found in many tiss, ie eyes, hair and skin

Synth in epidermins by pigment formin cells called melanocytes, where it protects the underlying cells from sunlight

89

MSG

Sodium salt of glutamic acid

enhances flavor of food, savory

some people have rxn to MSA and develop MSG symptom complex

symptoms attributed to effects of glutamate or its derivative on the CNS (GABA)