module: dmel_carnitine_biosynthesis
title: L-carnitine biosynthesis in Drosophila melanogaster
label: L-carnitine biosynthesis
module_type: METABOLIC_PATHWAY
description: >-
  L-carnitine carries long-chain fatty acids into mitochondria for
  beta-oxidation. In animals it is made from N6,N6,N6-trimethyllysine, released
  by degradation of proteins carrying methylated lysines, in four steps.
  Trimethyllysine dioxygenase (Tmlh) hydroxylates trimethyllysine to
  3-hydroxy-trimethyllysine; an aldolase cleaves this to
  4-trimethylaminobutyraldehyde and glycine; an aldehyde dehydrogenase oxidizes
  the aldehyde to gamma-butyrobetaine; and gamma-butyrobetaine dioxygenase
  hydroxylates gamma-butyrobetaine to carnitine. In Drosophila, CG10814 is the
  homolog of gamma-butyrobetaine dioxygenase, and the aldolase step is
  attributed to the threonine-aldolase-like protein CG10184 and to serine
  hydroxymethyltransferase (Shmt), which in mammals has
  hydroxytrimethyllysine aldolase activity.
summary: >-
  Four-step conversion of trimethyllysine to carnitine via Tmlh, an aldolase
  (CG10184 or Shmt) and the gamma-butyrobetaine dioxygenase homolog CG10814.
concepts:
  - {id: GO:0045329, label: carnitine biosynthetic process}
parts:
  - id: trimethyllysine_hydroxylation
    label: Trimethyllysine hydroxylation
    role: trimethyllysine to 3-hydroxy-trimethyllysine
    genes: [Tmlh]
    function: {id: GO:0050353, label: trimethyllysine dioxygenase activity}
  - id: hydroxytrimethyllysine_cleavage
    label: Hydroxytrimethyllysine aldol cleavage
    role: 3-hydroxy-trimethyllysine to 4-trimethylaminobutyraldehyde + glycine
    description: >-
      Candidate aldolases assigned to this step by FlyBase; neither has been
      shown biochemically to perform it in Drosophila.
    genes: [CG10184, Shmt]
    complex: false
  - id: butyrobetaine_hydroxylation
    label: gamma-Butyrobetaine hydroxylation
    role: gamma-butyrobetaine to carnitine
    description: >-
      CG10814 is a TauD-family 2-oxoglutarate-dependent hydroxylase with the
      gamma-butyrobetaine hydroxylase-like N-terminal domain.
    genes: [CG10814]
connections:
  - source: trimethyllysine_hydroxylation
    target: hydroxytrimethyllysine_cleavage
    connection_type: PRECEDES
    description: 3-hydroxy-trimethyllysine made by Tmlh is cleaved by the aldolase.
  - source: hydroxytrimethyllysine_cleavage
    target: butyrobetaine_hydroxylation
    connection_type: PRECEDES
    description: >-
      The aldehyde product is oxidized to gamma-butyrobetaine (by a dehydrogenase
      not assigned in this module), the substrate of the final hydroxylation.
knowledge_gaps:
  - gap_statement: >-
      Which enzyme performs the aldolase step (CG10184, Shmt or both) and which
      aldehyde dehydrogenase oxidizes 4-trimethylaminobutyraldehyde to
      gamma-butyrobetaine in Drosophila has not been established.
    boundary: Middle steps of carnitine biosynthesis from trimethyllysine.
    gap_kind: [BIOLOGY]
notes: >-
  Boundary. The module covers the four FlyBase members. The
  4-trimethylaminobutyraldehyde dehydrogenase step has no FlyBase member and
  is represented only in the connection between the aldolase and hydroxylase
  steps. Catalytic functions are assigned only to Tmlh; CG10184, Shmt and
  CG10814 carry no function in this module because their carnitine-pathway
  activities have not been shown for the fly proteins. Shmt is also a part of
  the glycine biosynthesis module.
group: CARNIBI