Download Biosynthesis of non-amino acids from amino acid precursors

Biosynthesis of non-amino acids from amino acid precursors
 Porphyrin Ring
 From glycine and succinyl-CoA
 Found in Hb, Myoglobin, cytochromes
 Cobalamin (vit B12) in non-mammals
 Steps:
 Condensation of succinyl-CoA and glycine (in mito); Yields deltaaminolevulinic acid
 Is RLS of heme bioshynthesis and enzyme (delta-aminolevulinic acid
synthase) is regulated: Heme inhibits activity and sythesis
 Formed aminolevuilinic acid exits mito and condenses with another molecule,
yielding cyclic porphobilinogen.
 Catalyzied by delta-aminolevuilinc acid dehydrase, and is sensitive to Pb
 High Pb: large amounts of aminolevulinic acid into urine, heme levels
drop
 Four Molecules of porphobilinogen cyclize, produce linear tetrapyrrole, then
cyclizes to generate uroporphyrinogen III.
 uroporphyrinogen III acted on by mito enzymes to form protoporphyrin IX, Fe
is added, and mature heme formed.
 Heme used as prosthetic gropu for Hb and cytochromes.
 Diseases called porphyries
 Individuals have lots of heme precursors (occurs when hemolyis occurs) and
bone marrow cells overproduce porphyrins to meet supply
 Conjugated ring structures excited by UV light, react w/ O2, form reactive
intermediates destroying skin cells
 Major problem is secondary skin infections by destruction. Scarring and loss
of extremeties. Sometimes have craving for blood (?).
 Old cells cleared by spleen and degraded
 Heme degraded to bilirubin, has yellow color
 Bilirubin deleiverd to liver bound to serum albumin, and conjugated to two
molecules of glucuronic acid (inc. solubility) and excreted as part of bile
 Buildup of bilirubin leads to yellow color and sign of liver problem.
 Seen in newborns, systems not set up yet, lights will destroy bilibrubin.
 Adults with hepatitis b/c cannot handle levels of bilirubin and conjugation
systems is defective
 Increase of indirect component (unconjugated bilirubin) signal of liver disease
 Regulatory aspects of Amino Acid degradation
 Principles straightforward: substrate availability, feedback inhibition, diet,
nitrogen flow, urea cycle
 Aminoacyl-tRNA synthetases
 Enzyme inovloved in linking AA to tRNA for protein synthesis have
lower Km than for degrative enzyme. Insure proteins made before AA are
degraded for energy storage.
 High levels activate first enzyme of pathway

High protein diets increase amount of degradative enzymes present, to convert
AA to energy stores.
 Alanine plays important role in carbon transfers btwn liver and muscle during AA
breakdown.
 Degradative conditions:
 Muscle protein degraded to individual AA.
 Transaminate with alpha-KG to form glutamate
 Glu will TA pyruvate to form alanine.
 Ala travels to liver, will be TA to pyruvate
 N group excreted as urea, and pyruvate converted to glucose.
 Principals governing Amio Acid Flux between tissues
 Affected by conditions which change the supply of fuels (overnight fast, mixed
meal, high protein) and by conditions that increase demand for AA (metabolic
acidosis, surgical stress, burns)
 Amonia (NH4+) is toxic
 Transported as alanine or glutamine. Released as Urea (see above).
 Pool of glutamine in blood serves several functions
 Provides ammonia for excretion of H in urine as NH4+
 Fuel for gut, kidney, cells of immune
 Source of N for rapidly dividng cells
 Formation of glutamine from gluatamate and NH4+ provides a means of
removing ammonia and transporting glutamate btwn cells in brain
 Prioritized: in metabolic acidosis kidney site of glutamine uptake; during
sepsis immune response site of glutamine uptake.
 The BCAA (Valine, leucine, isoleucine) form much of proteins, can
converted to TCA intermediates, and major precursors of glutamine.
Except for BCAA and ala, asp, glu, catabolism of AA occurs mainly in
liver
 Amino acids major gluconeogenic substrates, most energy obtained from
oxidation is from oxidation of glucose formed by them. Small percentage
of AA is converted to Acetyl-CoA or ketone.
 Rates of protein synthesis and degradation determine size of free amino
acid pools.
 As need or dietary state changes, pattern of AA flux changes by hormonal
response (insulin and glucagons( and physiological stress (glucocorticoids,
epi, triiodothyronine)
 Utlilization of Amino Acids in Tissues
 Require essential AA for protein synthesis
 Kidney
 Primary role of AA Nitrogen is provide ammonia in kidney for excretion
of protons in urine.
 NH4+ relased from glutamine by glutaminase and from glutamate by
glutamate DH, forming alpha-KG.
 Alpha-KG used as fuel by kidney and oxidized to CO2, convereted to
glucose for cells in renal medulla, or converted to Ala to return
ammonia to liver for urea synthesis
